Interventional Management in Hypertension
Interventional Management in Hypertension
As of 2014, several devices are available which use the ablation techniques covered above (Table 1), although none are currently approved for use outside research studies in the United States. The occurrence of significant back pain is common during renal denervation and conscious sedation is employed in these patients. The first system to see clinical use was Medtronic's Symplicity system (Symplicity Catheter, Medtronic, Minneapolis, MN), developed initially by Ardian, which was subsequently bought by Medtronic. As covered in Table 1, preliminary experience with the ablation technologies was extremely encouraging until the announcement by Medtronic, on 9 January 2014 [http://newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irol-newsArticle&ID=1889335&highlight=; accessed 5 April 2014], of the failure to meet the efficacy endpoint in the Symplicity HTN3 trial. This occurred at a time when the Symplicity system was approved for use in 88 countries in the world as of February 2014. The trial results for HTN3 were published concurrent with the late-breaking clinical trial presentation at the American College of Cardiology annual meeting in Washington D.C..
Briefly, this pivotal trial enrolled 535 patients with drug-resistant hypertension taking at least three antihypertensive drugs in maximum tolerated dosages. A total of 1441 patients were enrolled in the study and about 60% failed to meet all inclusion criteria as outlined in the design paper. The key features of this trial that differentiated it from all prior renal denervation trials were two-fold.
The first was the need to have patients qualify on the basis of an office systolic blood pressure of 160 mmHg or higher on two office visits, in addition to a 24-h ambulatory blood pressure monitor (ABPM) systolic blood pressure of more than 135 mmHg. The second was the presence of a sham control arm. The sham control arm is, and continues to be, a source of active discussion. When a patient was brought to the catheterization suite for the required prerandomization angiogram (anatomy requirements were covered above), they were given headphones for listening to music, a blindfold, and all were given conscious sedation. Exit interviews with the patients revealed that the majority (about 80%) could not tell whether or not they received the denervation procedure, or just the angiogram without the denervation.
Whereas prior Symplicity catheter trials demonstrated an office systolic blood pressure reduction of about 25 mmHg at 6 months, in HTN3 the reduction was 14 mmHg in the denervation arm, and 12 mmHg in the sham control arm. The systolic ABPM responses were 7 mmHg in the denervation arm and 5 mmHg in the sham control arm.
As a consequence of this, Medtronic released their top line efficacy data on 9 January 2014. Two other aspects deserve a mention. The first is that they more than met the safety endpoints, showing a significant adverse event rate of 1.4% in the denervation group, well below the 'bar' of 9.8% set by the protocol designers. Second, the efficacy data were confirmed by an independent statistical review.
Somewhat similar findings occurred with the announcement of the Rheos Pivotal trial. This investigation randomized 265 patients with drug-resistant hypertension to a different kind of 'sham' control. All patients received the device implantation with electrodes placed on both carotid bifurcations. Two-thirds (n = 181) had the device turned 'on' at 1 month after procedure and one-third (n = 84) did not have the device activated ('off') until 7 months after placement. Efficacy was determined at the 7 months after surgery, or said another way, after 6 months of being either 'on' or 'off', following a 1-month recovery period. There were five primary endpoints in the trial; two were based on efficacy [acute (6 months) versus sustained (1 year)] and three were based on safety (the operative intervention, the safety of baroreceptor activation therapy and the safety of the device itself). The 'off' group had a greater than expected reduction in office blood pressure compared with the 'on' group at 6 months. Fifty-four percentage of those in the 'on' compared with 46% of those in the 'off' responded to the procedure. In addition, the goal was to have 82% of patients free of adverse events at 30-day time point, whereas the actual figure was 75%. Thus, one efficacy endpoint and one safety endpoint were not met.
Where We Are Now?
As of 2014, several devices are available which use the ablation techniques covered above (Table 1), although none are currently approved for use outside research studies in the United States. The occurrence of significant back pain is common during renal denervation and conscious sedation is employed in these patients. The first system to see clinical use was Medtronic's Symplicity system (Symplicity Catheter, Medtronic, Minneapolis, MN), developed initially by Ardian, which was subsequently bought by Medtronic. As covered in Table 1, preliminary experience with the ablation technologies was extremely encouraging until the announcement by Medtronic, on 9 January 2014 [http://newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irol-newsArticle&ID=1889335&highlight=; accessed 5 April 2014], of the failure to meet the efficacy endpoint in the Symplicity HTN3 trial. This occurred at a time when the Symplicity system was approved for use in 88 countries in the world as of February 2014. The trial results for HTN3 were published concurrent with the late-breaking clinical trial presentation at the American College of Cardiology annual meeting in Washington D.C..
Briefly, this pivotal trial enrolled 535 patients with drug-resistant hypertension taking at least three antihypertensive drugs in maximum tolerated dosages. A total of 1441 patients were enrolled in the study and about 60% failed to meet all inclusion criteria as outlined in the design paper. The key features of this trial that differentiated it from all prior renal denervation trials were two-fold.
The first was the need to have patients qualify on the basis of an office systolic blood pressure of 160 mmHg or higher on two office visits, in addition to a 24-h ambulatory blood pressure monitor (ABPM) systolic blood pressure of more than 135 mmHg. The second was the presence of a sham control arm. The sham control arm is, and continues to be, a source of active discussion. When a patient was brought to the catheterization suite for the required prerandomization angiogram (anatomy requirements were covered above), they were given headphones for listening to music, a blindfold, and all were given conscious sedation. Exit interviews with the patients revealed that the majority (about 80%) could not tell whether or not they received the denervation procedure, or just the angiogram without the denervation.
Whereas prior Symplicity catheter trials demonstrated an office systolic blood pressure reduction of about 25 mmHg at 6 months, in HTN3 the reduction was 14 mmHg in the denervation arm, and 12 mmHg in the sham control arm. The systolic ABPM responses were 7 mmHg in the denervation arm and 5 mmHg in the sham control arm.
As a consequence of this, Medtronic released their top line efficacy data on 9 January 2014. Two other aspects deserve a mention. The first is that they more than met the safety endpoints, showing a significant adverse event rate of 1.4% in the denervation group, well below the 'bar' of 9.8% set by the protocol designers. Second, the efficacy data were confirmed by an independent statistical review.
Somewhat similar findings occurred with the announcement of the Rheos Pivotal trial. This investigation randomized 265 patients with drug-resistant hypertension to a different kind of 'sham' control. All patients received the device implantation with electrodes placed on both carotid bifurcations. Two-thirds (n = 181) had the device turned 'on' at 1 month after procedure and one-third (n = 84) did not have the device activated ('off') until 7 months after placement. Efficacy was determined at the 7 months after surgery, or said another way, after 6 months of being either 'on' or 'off', following a 1-month recovery period. There were five primary endpoints in the trial; two were based on efficacy [acute (6 months) versus sustained (1 year)] and three were based on safety (the operative intervention, the safety of baroreceptor activation therapy and the safety of the device itself). The 'off' group had a greater than expected reduction in office blood pressure compared with the 'on' group at 6 months. Fifty-four percentage of those in the 'on' compared with 46% of those in the 'off' responded to the procedure. In addition, the goal was to have 82% of patients free of adverse events at 30-day time point, whereas the actual figure was 75%. Thus, one efficacy endpoint and one safety endpoint were not met.
