Impact of Renal Denervation on 24-Hour Ambulatory BP
The design of SYMPLICITY HTN-3 was published previously. Briefly, patients 18 to 80 years old with resistant hypertension were randomized 2:1 to either renal artery denervation or a sham procedure and were followed for 6 months. All patients provided signed informed consent.
Patients on a stable antihypertensive drug regimen including maximally tolerated doses of ≥3 antihypertensive medications of complementary classes, including an appropriately dosed diuretic, were required to have seated office SBP ≥160 mm Hg (using the average of 3 measurements) at their first screening visit. For the 2 weeks before the second screening visit, patients recorded their home BP and kept a diary recording their adherence to medical therapy. Antihypertensive medication changes were not allowed during this 2-week period. At the second screening visit, the office SBP ≥160 mm Hg was confirmed, adherence with medications was documented, and 24-h ABPM was performed to ensure an ambulatory SBP ≥135 mm Hg. All ABPMs were performed with the Space Labs 24 Ambulatory Blood Pressure Monitoring System (Space Labs Medical, Issaquah, Washington). Patients were instructed to place the cuff on the same arm as used for office BP measurements, and the importance of leaving the cuff in place was stressed. The ABPM parameters were preset to measure BP every 30 min during the day (7:00 AM to 9:59 PM and for every 30 min at night (10:00 PM to 6:59 AM). Patients were instructed to engage in their normal daily activities and to hold their arm still by their side to avoid strenuous exercise during the device readings. All patients kept a diary that documented time to bed and time waking up, medications taken, and any other events of significance. On return of the ABPM machine, the patients' diaries were collected, and the ABPM data were downloaded to a computer. A 24-h ABPM was considered adequate if the number of successful daytime readings captured was at least 21 and the number of successful nighttime readings captured was at least 12. Only ABPMs with the pre-specified number of readings per protocol were included in the analysis.
Additional clinical exclusion criteria included known secondary causes of hypertension or more than 1 hospitalization for a hypertensive emergency in the past year. Anatomic exclusion criteria included >50% renal artery stenosis, renal artery aneurysm, prior renal artery intervention, multiple renal arteries, renal artery diameter <4 mm, or treatable segment <20 mm in length.
After undergoing a renal angiogram and an assessment of anatomy, patients were randomized to either renal artery denervation or the sham control group in a 2:1 ratio. Patients were followed for 6 months, at which time the primary and pre-specified powered ambulatory SBP secondary endpoints were assessed. Patients in the control group were then allowed to cross over to receive renal denervation treatment, if they still met the inclusion criteria for the study.
The renal denervation procedure used radiofrequency energy delivered by the Symplicity Renal Denervation System (Medtronic, Santa Rosa, California) to ablate the nerves within the main renal arteries. Patients were blinded to whether they received renal artery denervation or only renal angiography (sham). Assessors of BP and study personnel also were blinded to the treatment received by patients. Details of the blinding procedure and confirmation of adequate blinding have been provided previously. Antihypertensive medication changes were not allowed during the 6-month follow-up period unless clinically required.
The primary efficacy endpoint was a comparison of office SBP change from baseline to 6 months in the renal denervation group compared with the SBP change from baseline to 6 months in the sham control group and required a superiority margin of 5 mm Hg for success. The secondary efficacy endpoint was the change in mean 24-h ambulatory SBP at 6 months. In addition to 24-h ABPM, daytime and nighttime ambulatory BP differences from baseline to 6 months, as well as differences in the change between the 2 groups, were assessed. ABPM differences in BP and heart rate variability also were assessed at baseline and at 6 months for both groups.
The proportion of patients who were extreme dippers (decline of >20% in night to day BP), dippers (10% to 20% decline in night to day BP), nondippers (<10% decline in BP at night), and reverse dippers (night BP greater than day BP) were calculated at each follow-up visit.
For the current analysis, patients in each group were further categorized according to tertiles of baseline ambulatory SBP. Baseline and 6-month ABPM measurements were determined for each group.
The primary safety endpoint has been previously described and reported. Treated patients will be followed biannually, and non-crossover control patients will be followed annually through 5 years post-randomization.
The analyses were performed based on the intent-to-treat principle. The data were collected and analyzed by the sponsor (Medtronic, Minneapolis, Minnesota) and independently validated by Harvard Clinical Research Institute (Boston, Massachusetts). Means and standard deviations of continuous variables were presented by treatment group. Variability of ambulatory BP in each visit was defined as the standard deviation (SD) or coefficient of variation (%, 100 × SD/mean). Between group differences were compared using confidence intervals (CI) and evaluated using unpaired Student t tests. Within group differences from baseline to follow-up were evaluated using paired Student t tests. For categorical variables, the treatment group presented the counts and percentages. They were tested using the exact test for binary variables and chi-square test for multi-level categorical variables. All subgroups shown were pre-specified.
Differences within and between groups of early morning slope analysis also were calculated. Baseline ambulatory SBP was plotted against early morning time (3 AM to 8 AM), and the slopes of the regression lines were calculated for each group at baseline and at 6 months. The changes in slopes from baseline to 6 months for each group were compared using analysis of covariance.
Methods
The design of SYMPLICITY HTN-3 was published previously. Briefly, patients 18 to 80 years old with resistant hypertension were randomized 2:1 to either renal artery denervation or a sham procedure and were followed for 6 months. All patients provided signed informed consent.
Study Population
Patients on a stable antihypertensive drug regimen including maximally tolerated doses of ≥3 antihypertensive medications of complementary classes, including an appropriately dosed diuretic, were required to have seated office SBP ≥160 mm Hg (using the average of 3 measurements) at their first screening visit. For the 2 weeks before the second screening visit, patients recorded their home BP and kept a diary recording their adherence to medical therapy. Antihypertensive medication changes were not allowed during this 2-week period. At the second screening visit, the office SBP ≥160 mm Hg was confirmed, adherence with medications was documented, and 24-h ABPM was performed to ensure an ambulatory SBP ≥135 mm Hg. All ABPMs were performed with the Space Labs 24 Ambulatory Blood Pressure Monitoring System (Space Labs Medical, Issaquah, Washington). Patients were instructed to place the cuff on the same arm as used for office BP measurements, and the importance of leaving the cuff in place was stressed. The ABPM parameters were preset to measure BP every 30 min during the day (7:00 AM to 9:59 PM and for every 30 min at night (10:00 PM to 6:59 AM). Patients were instructed to engage in their normal daily activities and to hold their arm still by their side to avoid strenuous exercise during the device readings. All patients kept a diary that documented time to bed and time waking up, medications taken, and any other events of significance. On return of the ABPM machine, the patients' diaries were collected, and the ABPM data were downloaded to a computer. A 24-h ABPM was considered adequate if the number of successful daytime readings captured was at least 21 and the number of successful nighttime readings captured was at least 12. Only ABPMs with the pre-specified number of readings per protocol were included in the analysis.
Additional clinical exclusion criteria included known secondary causes of hypertension or more than 1 hospitalization for a hypertensive emergency in the past year. Anatomic exclusion criteria included >50% renal artery stenosis, renal artery aneurysm, prior renal artery intervention, multiple renal arteries, renal artery diameter <4 mm, or treatable segment <20 mm in length.
After undergoing a renal angiogram and an assessment of anatomy, patients were randomized to either renal artery denervation or the sham control group in a 2:1 ratio. Patients were followed for 6 months, at which time the primary and pre-specified powered ambulatory SBP secondary endpoints were assessed. Patients in the control group were then allowed to cross over to receive renal denervation treatment, if they still met the inclusion criteria for the study.
Study Procedure
The renal denervation procedure used radiofrequency energy delivered by the Symplicity Renal Denervation System (Medtronic, Santa Rosa, California) to ablate the nerves within the main renal arteries. Patients were blinded to whether they received renal artery denervation or only renal angiography (sham). Assessors of BP and study personnel also were blinded to the treatment received by patients. Details of the blinding procedure and confirmation of adequate blinding have been provided previously. Antihypertensive medication changes were not allowed during the 6-month follow-up period unless clinically required.
Endpoints
The primary efficacy endpoint was a comparison of office SBP change from baseline to 6 months in the renal denervation group compared with the SBP change from baseline to 6 months in the sham control group and required a superiority margin of 5 mm Hg for success. The secondary efficacy endpoint was the change in mean 24-h ambulatory SBP at 6 months. In addition to 24-h ABPM, daytime and nighttime ambulatory BP differences from baseline to 6 months, as well as differences in the change between the 2 groups, were assessed. ABPM differences in BP and heart rate variability also were assessed at baseline and at 6 months for both groups.
The proportion of patients who were extreme dippers (decline of >20% in night to day BP), dippers (10% to 20% decline in night to day BP), nondippers (<10% decline in BP at night), and reverse dippers (night BP greater than day BP) were calculated at each follow-up visit.
For the current analysis, patients in each group were further categorized according to tertiles of baseline ambulatory SBP. Baseline and 6-month ABPM measurements were determined for each group.
The primary safety endpoint has been previously described and reported. Treated patients will be followed biannually, and non-crossover control patients will be followed annually through 5 years post-randomization.
Statistical Analyses
The analyses were performed based on the intent-to-treat principle. The data were collected and analyzed by the sponsor (Medtronic, Minneapolis, Minnesota) and independently validated by Harvard Clinical Research Institute (Boston, Massachusetts). Means and standard deviations of continuous variables were presented by treatment group. Variability of ambulatory BP in each visit was defined as the standard deviation (SD) or coefficient of variation (%, 100 × SD/mean). Between group differences were compared using confidence intervals (CI) and evaluated using unpaired Student t tests. Within group differences from baseline to follow-up were evaluated using paired Student t tests. For categorical variables, the treatment group presented the counts and percentages. They were tested using the exact test for binary variables and chi-square test for multi-level categorical variables. All subgroups shown were pre-specified.
Differences within and between groups of early morning slope analysis also were calculated. Baseline ambulatory SBP was plotted against early morning time (3 AM to 8 AM), and the slopes of the regression lines were calculated for each group at baseline and at 6 months. The changes in slopes from baseline to 6 months for each group were compared using analysis of covariance.