Implanted Baroreflex Activation Device Fails Trial's Goals

NEW ORLEANS – A novel way to manage drug-resistant hypertension using an implanted device to deliver a small, continuous electrical current to both carotid sinuses will need more testing as results from a 265-patient pivotal trial failed to clearly prove efficacy.

The new trial results "justify further development" of baroreflex activation therapy, Dr. John D. Bisognano said April 5 at the meeting.

"This treatment is coming. The data were very encouraging. This is a modality that will work. I anticipate further studies to better define which patients get the greatest benefit," said Dr. Bisognano, director of cardiac rehabilitation and clinical preventive cardiology at the University of Rochester (N.Y.).

Cardiologists who heard the results had a mixed read on the potential role of this approach, which involved implanting a small device below the patient’s clavicle and placing a pair of electrical leads that wrap around the carotid sinus on each side of the patient’s neck. The device delivers a continuous electrical current of 1-6 volts to each carotid sinus, activating the reflex and producing a reduction in blood pressure in most patients.

"When the device becomes available, the greatest benefit will be in patients with end-stage renal failure. No matter what you do, their blood pressure does not go down," commented Dr. C. Venkata S. Ram, professor of medicine at the University of Texas Southwestern Medical Center in Dallas. "I just hope that patients tolerate" having leads in their necks, he added in an interview.

In the study results reported by Dr. Bisognano, 25% of the patients who received the device had at least one procedure-related adverse event within 30 days of device placement, including 4% with permanent nerve injury that resulted in numbness, dysphagia, or dysphonia; 5% with a transient nerve injury; 4% with a surgical complication (most of which resolved); and 3% with respiratory complaints (all of which resolved). Overall, 76% of the adverse events resolved, but about 2% of patients required explant of the device.

Dr. Prakash C. Deedwania took a more skeptical view of the approach. "This device would require battery changes and is subject to malfunctions. In my opinion, renal artery denervation is probably better, right now, for patients with treatment-resistant hypertension." The current study’s design also "left many unanswered questions," said Dr. Deedwania, professor of medicine at the University of California, San Francisco, in Fresno.

Patients enrolled in the study should have been thoroughly assessed for neuroendocrine hypertension. About a third of patients with treatment-resistant hypertension have a neuroendocrine cause, he noted.

The study’s design also left unclear how many enrolled patients were truly treatment resistant. One month on stable treatment with at least three drugs may not identify patients who are unresponsive to drugs, as some drugs, such as the direct renin inhibitor aliskiren, take longer than 1 month to start having a complete effect, he said.

In addition, current hypertension treatment guidelines from the American Heart Association call for using a mineralocorticoid receptor antagonist such as spironolactone or amiloride in patients with persistent hypertension that remains unresponsive to combinations of other drugs (Hypertension 2008;51:1403-19). The current report gives no information on whether all enrolled patients had first received spironolactone, a very inexpensive drug that often works in otherwise unresponsive patients, Dr. Deedwania said.

The pivotal study for the Rheos baroreflex activation device enrolled patients at 37 U.S. sites and two centers in Europe. All 265 patients who were enrolled received placement of the device. One month after surgery, a 2:1 randomization scheme led to blinded activation of the device in 181 patients and no activation in the other 84. Six months later, the researchers activated all the devices.

The patients averaged 54 years old, about 60% were men, and about three-quarters were white. Participants had failed to have their blood pressure controlled by an average of five drugs, and they had been on a stable regimen for at least a month at the time of entry. During the course of the study their treating physicians could freely change antihypertensive drug dosages and also add or remove drugs. Their systolic and diastolic blood pressure at baseline averaged about 177/103 mm Hg, and their heart rate averaged 74 beats/min. To qualify for the study, patients needed a minimum blood pressure of at least 160/80 mm Hg, a 24-hour average ambulatory pressure of at least 135 mm Hg, and they had to be on at least three antihypertensive medications.

The study included five primary end points, with a prespecified definition of success for each of the end point.

One end point assessed short-term response after 6 months, defining success as at least a 10-mm Hg drop in systolic pressure, compared with baseline. This criteria for success occurred in 54% of patients with an activated device in the study’s first 6 months and in 46% of those with an inactive device, an 8% difference in response rate between the active and control arms that failed to meet the prespecified goal of a 20% difference. Dr. Bisognano speculated that the placebo response may have been so high because of continued drug treatment optimization during this period.

The second end point assessed the 12-month response in all 265 patients, again using a 10-mm Hg drop in systolic pressure relative to baseline as the criterion for a positive response. This reduction occurred in 88% of patients, surpassing the prespecified success threshold of 65%.

The third end point focused on 30-day safety. The 25% of patients with an adverse event exceeded the prespecified threshold of 18%.

The fourth end point looked at safety at 6 months, with an adverse-event threshold in the active-treatment arm of no more than 15% greater than in the control arm. The results showed that patients receiving activation had a 2% reduced rate of adverse events, compared with the inactive, control arm, which meant the results fulfilled this criterion of success.

The fifth end point looked at the overall adverse event rate on active therapy in all 265 patients after 12 months. The 13% actual rate fell within the prespecified goal of less than 28%, meaning the results fulfilled this criterion of success.

The study also assessed efficacy another way, by tallying the percentage of patients whose systolic pressure dropped below 140 mm Hg. At the 6-month mark, this degree of blood pressure reduction occurred in 42% of patients receiving activation and in 24% of patients whose device had not yet been activated, a statistically significant difference. At the 12-month mark, 53% of the patients on continuous active treatment and 51% of those who switched from 6 months off treatment to 6 months on treatment reached this systolic pressure goal.

In addition, the study included an echocardiography substudy designed to assess the impact of baroreflex activation on left ventricular mass and shape. At baseline, these 60 patients had an average left ventricular mass index of 117 kg/m². A year later, the average had dropped to 102 kg/m², a statistically significant difference. Patients also shifted toward having more normalized left ventricular shapes, Dr. Bisognano reported in a separate talk at the meeting.

Dr. Bisognano said that he has received consulting fees or honoraria from CVrx, the company that is developing the carotid baroreflex activation device. Dr. Ram said that he has served on the speakers’ bureau for the Peer Group and for Advanced Health Media. Dr. Deedwania said that he had no disclosures.

NEW ORLEANS – A novel way to manage drug-resistant hypertension using an implanted device to deliver a small, continuous electrical current to both carotid sinuses will need more testing as results from a 265-patient pivotal trial failed to clearly prove efficacy.

The new trial results "justify further development" of baroreflex activation therapy, Dr. John D. Bisognano said April 5 at the meeting.

"This treatment is coming. The data were very encouraging. This is a modality that will work. I anticipate further studies to better define which patients get the greatest benefit," said Dr. Bisognano, director of cardiac rehabilitation and clinical preventive cardiology at the University of Rochester (N.Y.).

Cardiologists who heard the results had a mixed read on the potential role of this approach, which involved implanting a small device below the patient’s clavicle and placing a pair of electrical leads that wrap around the carotid sinus on each side of the patient’s neck. The device delivers a continuous electrical current of 1-6 volts to each carotid sinus, activating the reflex and producing a reduction in blood pressure in most patients.

"When the device becomes available, the greatest benefit will be in patients with end-stage renal failure. No matter what you do, their blood pressure does not go down," commented Dr. C. Venkata S. Ram, professor of medicine at the University of Texas Southwestern Medical Center in Dallas. "I just hope that patients tolerate" having leads in their necks, he added in an interview.

In the study results reported by Dr. Bisognano, 25% of the patients who received the device had at least one procedure-related adverse event within 30 days of device placement, including 4% with permanent nerve injury that resulted in numbness, dysphagia, or dysphonia; 5% with a transient nerve injury; 4% with a surgical complication (most of which resolved); and 3% with respiratory complaints (all of which resolved). Overall, 76% of the adverse events resolved, but about 2% of patients required explant of the device.

Dr. Prakash C. Deedwania took a more skeptical view of the approach. "This device would require battery changes and is subject to malfunctions. In my opinion, renal artery denervation is probably better, right now, for patients with treatment-resistant hypertension." The current study’s design also "left many unanswered questions," said Dr. Deedwania, professor of medicine at the University of California, San Francisco, in Fresno.

Patients enrolled in the study should have been thoroughly assessed for neuroendocrine hypertension. About a third of patients with treatment-resistant hypertension have a neuroendocrine cause, he noted.

The study’s design also left unclear how many enrolled patients were truly treatment resistant. One month on stable treatment with at least three drugs may not identify patients who are unresponsive to drugs, as some drugs, such as the direct renin inhibitor aliskiren, take longer than 1 month to start having a complete effect, he said.

In addition, current hypertension treatment guidelines from the American Heart Association call for using a mineralocorticoid receptor antagonist such as spironolactone or amiloride in patients with persistent hypertension that remains unresponsive to combinations of other drugs (Hypertension 2008;51:1403-19). The current report gives no information on whether all enrolled patients had first received spironolactone, a very inexpensive drug that often works in otherwise unresponsive patients, Dr. Deedwania said.

The pivotal study for the Rheos baroreflex activation device enrolled patients at 37 U.S. sites and two centers in Europe. All 265 patients who were enrolled received placement of the device. One month after surgery, a 2:1 randomization scheme led to blinded activation of the device in 181 patients and no activation in the other 84. Six months later, the researchers activated all the devices.

The patients averaged 54 years old, about 60% were men, and about three-quarters were white. Participants had failed to have their blood pressure controlled by an average of five drugs, and they had been on a stable regimen for at least a month at the time of entry. During the course of the study their treating physicians could freely change antihypertensive drug dosages and also add or remove drugs. Their systolic and diastolic blood pressure at baseline averaged about 177/103 mm Hg, and their heart rate averaged 74 beats/min. To qualify for the study, patients needed a minimum blood pressure of at least 160/80 mm Hg, a 24-hour average ambulatory pressure of at least 135 mm Hg, and they had to be on at least three antihypertensive medications.

The study included five primary end points, with a prespecified definition of success for each of the end point.

One end point assessed short-term response after 6 months, defining success as at least a 10-mm Hg drop in systolic pressure, compared with baseline. This criteria for success occurred in 54% of patients with an activated device in the study’s first 6 months and in 46% of those with an inactive device, an 8% difference in response rate between the active and control arms that failed to meet the prespecified goal of a 20% difference. Dr. Bisognano speculated that the placebo response may have been so high because of continued drug treatment optimization during this period.

The second end point assessed the 12-month response in all 265 patients, again using a 10-mm Hg drop in systolic pressure relative to baseline as the criterion for a positive response. This reduction occurred in 88% of patients, surpassing the prespecified success threshold of 65%.

The third end point focused on 30-day safety. The 25% of patients with an adverse event exceeded the prespecified threshold of 18%.

The fourth end point looked at safety at 6 months, with an adverse-event threshold in the active-treatment arm of no more than 15% greater than in the control arm. The results showed that patients receiving activation had a 2% reduced rate of adverse events, compared with the inactive, control arm, which meant the results fulfilled this criterion of success.

The fifth end point looked at the overall adverse event rate on active therapy in all 265 patients after 12 months. The 13% actual rate fell within the prespecified goal of less than 28%, meaning the results fulfilled this criterion of success.

The study also assessed efficacy another way, by tallying the percentage of patients whose systolic pressure dropped below 140 mm Hg. At the 6-month mark, this degree of blood pressure reduction occurred in 42% of patients receiving activation and in 24% of patients whose device had not yet been activated, a statistically significant difference. At the 12-month mark, 53% of the patients on continuous active treatment and 51% of those who switched from 6 months off treatment to 6 months on treatment reached this systolic pressure goal.

In addition, the study included an echocardiography substudy designed to assess the impact of baroreflex activation on left ventricular mass and shape. At baseline, these 60 patients had an average left ventricular mass index of 117 kg/m². A year later, the average had dropped to 102 kg/m², a statistically significant difference. Patients also shifted toward having more normalized left ventricular shapes, Dr. Bisognano reported in a separate talk at the meeting.

Dr. Bisognano said that he has received consulting fees or honoraria from CVrx, the company that is developing the carotid baroreflex activation device. Dr. Ram said that he has served on the speakers’ bureau for the Peer Group and for Advanced Health Media. Dr. Deedwania said that he had no disclosures.

NEW ORLEANS – A novel way to manage drug-resistant hypertension using an implanted device to deliver a small, continuous electrical current to both carotid sinuses will need more testing as results from a 265-patient pivotal trial failed to clearly prove efficacy.

The new trial results "justify further development" of baroreflex activation therapy, Dr. John D. Bisognano said April 5 at the meeting.

"This treatment is coming. The data were very encouraging. This is a modality that will work. I anticipate further studies to better define which patients get the greatest benefit," said Dr. Bisognano, director of cardiac rehabilitation and clinical preventive cardiology at the University of Rochester (N.Y.).

Cardiologists who heard the results had a mixed read on the potential role of this approach, which involved implanting a small device below the patient’s clavicle and placing a pair of electrical leads that wrap around the carotid sinus on each side of the patient’s neck. The device delivers a continuous electrical current of 1-6 volts to each carotid sinus, activating the reflex and producing a reduction in blood pressure in most patients.

"When the device becomes available, the greatest benefit will be in patients with end-stage renal failure. No matter what you do, their blood pressure does not go down," commented Dr. C. Venkata S. Ram, professor of medicine at the University of Texas Southwestern Medical Center in Dallas. "I just hope that patients tolerate" having leads in their necks, he added in an interview.

In the study results reported by Dr. Bisognano, 25% of the patients who received the device had at least one procedure-related adverse event within 30 days of device placement, including 4% with permanent nerve injury that resulted in numbness, dysphagia, or dysphonia; 5% with a transient nerve injury; 4% with a surgical complication (most of which resolved); and 3% with respiratory complaints (all of which resolved). Overall, 76% of the adverse events resolved, but about 2% of patients required explant of the device.

Dr. Prakash C. Deedwania took a more skeptical view of the approach. "This device would require battery changes and is subject to malfunctions. In my opinion, renal artery denervation is probably better, right now, for patients with treatment-resistant hypertension." The current study’s design also "left many unanswered questions," said Dr. Deedwania, professor of medicine at the University of California, San Francisco, in Fresno.

Patients enrolled in the study should have been thoroughly assessed for neuroendocrine hypertension. About a third of patients with treatment-resistant hypertension have a neuroendocrine cause, he noted.

The study’s design also left unclear how many enrolled patients were truly treatment resistant. One month on stable treatment with at least three drugs may not identify patients who are unresponsive to drugs, as some drugs, such as the direct renin inhibitor aliskiren, take longer than 1 month to start having a complete effect, he said.

In addition, current hypertension treatment guidelines from the American Heart Association call for using a mineralocorticoid receptor antagonist such as spironolactone or amiloride in patients with persistent hypertension that remains unresponsive to combinations of other drugs (Hypertension 2008;51:1403-19). The current report gives no information on whether all enrolled patients had first received spironolactone, a very inexpensive drug that often works in otherwise unresponsive patients, Dr. Deedwania said.

The pivotal study for the Rheos baroreflex activation device enrolled patients at 37 U.S. sites and two centers in Europe. All 265 patients who were enrolled received placement of the device. One month after surgery, a 2:1 randomization scheme led to blinded activation of the device in 181 patients and no activation in the other 84. Six months later, the researchers activated all the devices.

The patients averaged 54 years old, about 60% were men, and about three-quarters were white. Participants had failed to have their blood pressure controlled by an average of five drugs, and they had been on a stable regimen for at least a month at the time of entry. During the course of the study their treating physicians could freely change antihypertensive drug dosages and also add or remove drugs. Their systolic and diastolic blood pressure at baseline averaged about 177/103 mm Hg, and their heart rate averaged 74 beats/min. To qualify for the study, patients needed a minimum blood pressure of at least 160/80 mm Hg, a 24-hour average ambulatory pressure of at least 135 mm Hg, and they had to be on at least three antihypertensive medications.

The study included five primary end points, with a prespecified definition of success for each of the end point.

One end point assessed short-term response after 6 months, defining success as at least a 10-mm Hg drop in systolic pressure, compared with baseline. This criteria for success occurred in 54% of patients with an activated device in the study’s first 6 months and in 46% of those with an inactive device, an 8% difference in response rate between the active and control arms that failed to meet the prespecified goal of a 20% difference. Dr. Bisognano speculated that the placebo response may have been so high because of continued drug treatment optimization during this period.

The second end point assessed the 12-month response in all 265 patients, again using a 10-mm Hg drop in systolic pressure relative to baseline as the criterion for a positive response. This reduction occurred in 88% of patients, surpassing the prespecified success threshold of 65%.

The third end point focused on 30-day safety. The 25% of patients with an adverse event exceeded the prespecified threshold of 18%.

The fourth end point looked at safety at 6 months, with an adverse-event threshold in the active-treatment arm of no more than 15% greater than in the control arm. The results showed that patients receiving activation had a 2% reduced rate of adverse events, compared with the inactive, control arm, which meant the results fulfilled this criterion of success.

The fifth end point looked at the overall adverse event rate on active therapy in all 265 patients after 12 months. The 13% actual rate fell within the prespecified goal of less than 28%, meaning the results fulfilled this criterion of success.

The study also assessed efficacy another way, by tallying the percentage of patients whose systolic pressure dropped below 140 mm Hg. At the 6-month mark, this degree of blood pressure reduction occurred in 42% of patients receiving activation and in 24% of patients whose device had not yet been activated, a statistically significant difference. At the 12-month mark, 53% of the patients on continuous active treatment and 51% of those who switched from 6 months off treatment to 6 months on treatment reached this systolic pressure goal.

In addition, the study included an echocardiography substudy designed to assess the impact of baroreflex activation on left ventricular mass and shape. At baseline, these 60 patients had an average left ventricular mass index of 117 kg/m². A year later, the average had dropped to 102 kg/m², a statistically significant difference. Patients also shifted toward having more normalized left ventricular shapes, Dr. Bisognano reported in a separate talk at the meeting.

Dr. Bisognano said that he has received consulting fees or honoraria from CVrx, the company that is developing the carotid baroreflex activation device. Dr. Ram said that he has served on the speakers’ bureau for the Peer Group and for Advanced Health Media. Dr. Deedwania said that he had no disclosures.