Hypertension, Resistant to Conventional Therapy
Conditions
Keywords
Hypertension, Catheter Ablation, Renal Nerves
Brief summary
Objective of this study is to evaluate whether a distal mode of endovascular renal denervation with the treatment performed primarily in segmental branches of renal artery is more effective than conventional mode of the intervention with the treatment equally distributed within its main trunk for the treatment of drug-resistant hypertension.
Detailed description
Recent spectacular failure of renal denervation (RDN) therapy in SymplicityHTN-3 trial in fact might be easily predicted from the very beginning. Conventional RDN done as 4-6 point treatments equally distributed within main trunk of renal artery (RA) may only be effective if renal plexus tightly surrounds the artery throughout its whole course with equal longitudinal and circumferential density of the nerve fibers. While this idea itself is unnaturally idealistic also a number of surgical studies demonstrated that proximally majority of renal nerves go at a distance from RA obliquely to its course and join the artery mainly in its distal part (fan-shaped renal plexus with wide base directed toward aorta and apex converging to renal gate). We developed a distal mode of RDN targeting segmental branches of RA and conducted a single-center double-blind randomized controlled parallel group study to compare its efficacy and safety to those of conventional RDN in patients with drug-resistant hypertension.
Interventions
PROCEDUREDistal renal denervation
Percutaneous endovascular intervention when catheter-based electrode (Symplicity Flex; Medtronic, Inc.) is used for stepwise radiofrequency energy delivery to segmental branches of the renal artery in a number of points distributed along the length and circumference of the vessels in order to ablate renal nerve plexus
PROCEDUREConventional renal denervation
Percutaneous endovascular intervention when catheter-based electrode (Symplicity Flex; Medtronic, Inc.) is used for stepwise radiofrequency energy delivery to the main trunk of the renal artery in a number of points equally distributed along its length and circumference in order to ablate renal nerve plexus
Sponsors
Tomsk National Research Medical Center of the Russian Academy of Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* systolic BP is equal or greater than 160 mmHg or diastolic BP is equal or greater than 100 mmHg, * stable (\>3 months) treatment with full doses of at least 3 antihypertensive drugs including a diuretic, * given written informed consent
Exclusion criteria
* secondary hypertension * 24h-mean systolic BP \<135 mmHg, * estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2, * extended disease of renal artery, * any other clinically important disorders/comorbidities significantly increasing risk of endovascular intervention (investigator's assessment)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Changes of 24h-mean Systolic BP Assessed by Ambulatory Blood Pressure Monitoring (ABPM) | From baseline to 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes of Office Diastolic BP | From baseline to 6 months | — |
| Changes of Daytime Systolic BP | From baseline to 6 months | — |
| Changes of Daytime Mean Systolic BP | From baseline to 12 months | — |
| Changes of Daytime Mean Diastolic BP | From baseline to 6 months | — |
| Changes of Nighttime Mean Systolic BP | From baseline to 6 months | — |
| Changes of Nighttime Mean Diastolic BP | From baseline to 6 months | — |
| Changes of Office Systolic BP | From baseline to 6 months | — |
| Changes of 24h-mean Diastolic BP | From baseline to 6 months | — |
| Changes of 24h-mean Systolic BP | From baseline to 12 months | — |
| Number of Adverse Events | From baseline to 6 months | — |
| Changes of Arterial Resistance Index Measured by Doppler Flowmetry in the Right Segmental Renal Arteries | From baseline to 6 months | Resistance index is calculated as the relative difference between a peak systolic and end diastolic blood flow velocities assessed by ultrasound Doppler flowmetry |
| Changes of Arterial Resistance Index Measured by Doppler Flowmetry in the Left Segmental Renal Arteries | From baseline to 6 months | Resistance index calculated as the relative difference between a peak systolic and end diastolic blood flow velocities assessed by ultrasound Doppler flowmetry |
| Changes of Serum Creatinine | From baseline to 6 months | — |
| Changes of Estimated Glomerular Filtration Rate (eGFR) | From baseline to 6 months | — |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Distal Renal Denervation Endovascular denervation of segmental branches of renal artery | 28 |
| Conventional Renal Denervation Endovascular denervation of main trunk of renal artery | 27 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Distal Renal Denervation | Total | Conventional Renal Denervation |
|---|---|---|---|
| 24-hour diastolic BP | 91.6 mmHg STANDARD_DEVIATION 19.1 | 89.6 mmHg STANDARD_DEVIATION 18.2 | 88.0 mmHg STANDARD_DEVIATION 19.6 |
| 24-hour proteinuria | 0.12 g STANDARD_DEVIATION 0.19 | 0.15 g STANDARD_DEVIATION 0.25 | 0.16 g STANDARD_DEVIATION 0.3 |
| 24-hour systolic BP | 168.0 mmHg STANDARD_DEVIATION 24.1 | 162.6 mmHg STANDARD_DEVIATION 20.6 | 158.0 mmHg STANDARD_DEVIATION 15.2 |
| Age, Continuous | 56.5 years STANDARD_DEVIATION 9.4 | 56.9 years STANDARD_DEVIATION 9.4 | 57.3 years STANDARD_DEVIATION 9.5 |
| A number of antihypertensive drugs taken | 4.1 Medication (single active ingredient) STANDARD_DEVIATION 1.1 | 4.2 Medication (single active ingredient) STANDARD_DEVIATION 1 | 4.3 Medication (single active ingredient) STANDARD_DEVIATION 0.9 |
| A use of diuretics | 27 Participants | 54 Participants | 27 Participants |
| Concomitant coronary artery disease (CAD) | 12 Participants | 24 Participants | 12 Participants |
| Concomitant diabetes | 14 Participants | 27 Participants | 13 Participants |
| estimated glomerular filtration rate (eGFR) | 79.3 ml/min/m2 STANDARD_DEVIATION 24 | 77.3 ml/min/m2 STANDARD_DEVIATION 20 | 70.6 ml/min/m2 STANDARD_DEVIATION 13.1 |
| Left ventricular mass | 260.3 g STANDARD_DEVIATION 68.6 | 260.1 g STANDARD_DEVIATION 76.1 | 259.8 g STANDARD_DEVIATION 84.5 |
| Office diastolic BP | 93.4 mmHg STANDARD_DEVIATION 17.3 | 93.8 mmHg STANDARD_DEVIATION 18.3 | 94.2 mmHg STANDARD_DEVIATION 19.6 |
| Office systolic BP | 170.8 mmHg STANDARD_DEVIATION 23 | 170.1 mmHg STANDARD_DEVIATION 23.1 | 169.4 mmHg STANDARD_DEVIATION 23.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 52 Participants | 25 Participants |
| Region of Enrollment Russia | 28 participants | 55 participants | 27 participants |
| Serum creatinine | 79.3 mMol/L STANDARD_DEVIATION 24 | 84.2 mMol/L STANDARD_DEVIATION 22.8 | 89.4 mMol/L STANDARD_DEVIATION 20.7 |
| Sex: Female, Male Female | 18 Participants | 35 Participants | 17 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 27 | 0 / 24 |
| serious Total, serious adverse events | 1 / 27 | 0 / 24 |
Outcome results
Primary
Changes of 24h-mean Systolic BP Assessed by Ambulatory Blood Pressure Monitoring (ABPM)
Time frame: From baseline to 6 months
Population: The subjects who completed 6 months follow up without serious violations of the study protocol - per protocol set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of 24h-mean Systolic BP Assessed by Ambulatory Blood Pressure Monitoring (ABPM) | 21.1 mmHg | Standard Deviation 19.3 |
| Conventional Renal Denervation | Changes of 24h-mean Systolic BP Assessed by Ambulatory Blood Pressure Monitoring (ABPM) | 10.3 mmHg | Standard Deviation 17.8 |
p-value: 0.04595% CI: [0.3, 21.4]t-test, 2 sided
Secondary
Changes of 24h-mean Diastolic BP
Time frame: From baseline to 12 months
Population: ITT analysis by Last Observation Carried Forward (LOCF) method in the subjects with the available data . (Six month data were used in 4 late (\>6 months) dropouts and also in 1 patient without 12 month' ABPM, 1 month data were used in 2 early (\<6 months) dropouts. One patient had no post procedure data at all and was excluded from analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of 24h-mean Diastolic BP | 11.2 mmHg | Standard Deviation 12.3 |
| Conventional Renal Denervation | Changes of 24h-mean Diastolic BP | 7.9 mmHg | Standard Deviation 10.6 |
p-value: 0.304t-test, 2 sided
Secondary
Changes of 24h-mean Diastolic BP
Time frame: From baseline to 6 months
Population: PPS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of 24h-mean Diastolic BP | 11.1 mmHg | Standard Deviation 11.9 |
| Conventional Renal Denervation | Changes of 24h-mean Diastolic BP | 7.0 mmHg | Standard Deviation 10.6 |
p-value: 0.213t-test, 2 sided
Secondary
Changes of 24h-mean Systolic BP
Time frame: From baseline to 12 months
Population: ITT analysis by Last Observation Carried Forward (LOCF) method in the subjects with the available data . (Six month data were used in 4 late (\>6 months) dropouts and also in 1 patient without 12 month' ABPM, 1 month data were used in 2 early (\<6 months) dropouts. One patient had no post procedure data at all and was excluded from analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of 24h-mean Systolic BP | 22.1 mmHg | Standard Deviation 20.6 |
| Conventional Renal Denervation | Changes of 24h-mean Systolic BP | 11.5 mmHg | Standard Deviation 16.4 |
p-value: 0.041t-test, 2 sided
Secondary
Changes of Arterial Resistance Index Measured by Doppler Flowmetry in the Left Segmental Renal Arteries
Resistance index calculated as the relative difference between a peak systolic and end diastolic blood flow velocities assessed by ultrasound Doppler flowmetry
Time frame: From baseline to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Arterial Resistance Index Measured by Doppler Flowmetry in the Left Segmental Renal Arteries | 0.006 ratio | Standard Deviation 0.066 |
| Conventional Renal Denervation | Changes of Arterial Resistance Index Measured by Doppler Flowmetry in the Left Segmental Renal Arteries | 0.032 ratio | Standard Deviation 0.066 |
p-value: 0.203t-test, 2 sided
Secondary
Changes of Arterial Resistance Index Measured by Doppler Flowmetry in the Right Segmental Renal Arteries
Resistance index is calculated as the relative difference between a peak systolic and end diastolic blood flow velocities assessed by ultrasound Doppler flowmetry
Time frame: From baseline to 6 months
Population: Per protocol set (PPS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Arterial Resistance Index Measured by Doppler Flowmetry in the Right Segmental Renal Arteries | 0.018 ratio | Standard Deviation 0.064 |
| Conventional Renal Denervation | Changes of Arterial Resistance Index Measured by Doppler Flowmetry in the Right Segmental Renal Arteries | 0.017 ratio | Standard Deviation 0.058 |
p-value: 0.96t-test, 2 sided
Secondary
Changes of Daytime Mean Diastolic BP
Time frame: From baseline to 6 months
Population: PPS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Daytime Mean Diastolic BP | 11.8 mmHg | Standard Deviation 12.9 |
| Conventional Renal Denervation | Changes of Daytime Mean Diastolic BP | 10.9 mmHg | Standard Deviation 18.9 |
p-value: 0.204t-test, 2 sided
Secondary
Changes of Daytime Mean Diastolic BP
Time frame: From baseline to 12 months
Population: ITT analysis by Last Observation Carried Forward (LOCF). (Six month data were used in 4 late (\>6 months) dropouts and also in 1 patient without 12 month' ABPM, 1 month data were used in 2 early (\<6 months) dropouts. One patient had no post procedure data at all and was excluded from analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Daytime Mean Diastolic BP | 11.3 mmHg | Standard Deviation 12.6 |
| Conventional Renal Denervation | Changes of Daytime Mean Diastolic BP | 7.9 mmHg | Standard Deviation 12.3 |
p-value: 0.324t-test, 2 sided
Secondary
Changes of Daytime Mean Systolic BP
Time frame: From baseline to 12 months
Population: ITT analysis by Last Observation Carried Forward (LOCF) method. (Six month data were used in 4 late (\>6 months) dropouts and also in 1 patient without 12 month' ABPM, 1 month data were used in 2 early (\<6 months) dropouts. One patient had no post procedure data at all and was excluded from analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Daytime Mean Systolic BP | 22.1 mmHg | Standard Deviation 20.5 |
| Conventional Renal Denervation | Changes of Daytime Mean Systolic BP | 11.5 mmHg | Standard Deviation 18.6 |
p-value: 0.054t-test, 2 sided
Secondary
Changes of Daytime Systolic BP
Time frame: From baseline to 6 months
Population: PPS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Daytime Systolic BP | 22.2 mmHg | Standard Deviation 19.9 |
| Conventional Renal Denervation | Changes of Daytime Systolic BP | 10.9 mmHg | Standard Deviation 18.9 |
p-value: 0.04t-test, 2 sided
Secondary
Changes of Estimated Glomerular Filtration Rate (eGFR)
Time frame: From baseline to 12 months
Population: ITT analysis by Last Observation Carried Forward (LOCF) method in the subjects with the available data. (Six month data were used in 4 late (\>6 months) dropouts and also in 1 patient without 12 month' ABPM, 1 month data were used in 2 early (\<6 months) dropouts. One patient had no post procedure data at all and was excluded from analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Estimated Glomerular Filtration Rate (eGFR) | -7.6 ml/min/square meter | Standard Deviation 13.6 |
| Conventional Renal Denervation | Changes of Estimated Glomerular Filtration Rate (eGFR) | -1.3 ml/min/square meter | Standard Deviation 12.5 |
Secondary
Changes of Estimated Glomerular Filtration Rate (eGFR)
Time frame: From baseline to 6 months
Population: The subjects with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Estimated Glomerular Filtration Rate (eGFR) | 7.6 ml/min/square meter | Standard Deviation 13.6 |
| Conventional Renal Denervation | Changes of Estimated Glomerular Filtration Rate (eGFR) | 1.3 ml/min/square meter | Standard Deviation 12.5 |
Secondary
Changes of Nighttime Mean Diastolic BP
Time frame: From baseline to 12 months
Population: ITT analysis by Last Observation Carried Forward (LOCF) method in the subjects with the available data. (6 month data were used in 4 late (\>6 months) dropouts and also in 1 patient without 12 month' ABPM, 1 month data were used in 2 early (\<6 months) dropouts. One patient had no post procedure data at all and was excluded from analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Nighttime Mean Diastolic BP | 7.2 mmHg | Standard Deviation 12.5 |
| Conventional Renal Denervation | Changes of Nighttime Mean Diastolic BP | 7.5 mmHg | Standard Deviation 12.1 |
p-value: 0.37t-test, 2 sided
Secondary
Changes of Nighttime Mean Diastolic BP
Time frame: From baseline to 6 months
Population: PPS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Nighttime Mean Diastolic BP | 6.7 mmHg | Standard Deviation 12.8 |
| Conventional Renal Denervation | Changes of Nighttime Mean Diastolic BP | 6.5 mmHg | Standard Deviation 11.8 |
p-value: 0.969t-test, 2 sided
Secondary
Changes of Nighttime Mean Systolic BP
Time frame: From baseline to 12 months
Population: ITT analysis by Last Observation Carried Forward (LOCF) method in the subjects with the available data. (Six month data were used in 4 late (\>6 months) dropouts and also in 1 patient without 12 month' ABPM, 1 month data were used in 2 early (\<6 months) dropouts. One patient had no post procedure data at all and was excluded from analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Nighttime Mean Systolic BP | 17.8 mmHg | Standard Deviation 22 |
| Conventional Renal Denervation | Changes of Nighttime Mean Systolic BP | 10.9 mmHg | Standard Deviation 19.2 |
p-value: 0.238t-test, 2 sided
Secondary
Changes of Nighttime Mean Systolic BP
Time frame: From baseline to 6 months
Population: PPS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Nighttime Mean Systolic BP | 16.5 mmHg | Standard Deviation 19.7 |
| Conventional Renal Denervation | Changes of Nighttime Mean Systolic BP | 9.3 mmHg | Standard Deviation 20.9 |
p-value: 0.217t-test, 2 sided
Secondary
Changes of Office Diastolic BP
Time frame: From baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Office Diastolic BP | 12.8 mmHg | Standard Deviation 15.7 |
| Conventional Renal Denervation | Changes of Office Diastolic BP | 10.8 mmHg | Standard Deviation 18.8 |
p-value: 0.66t-test, 2 sided
Secondary
Changes of Office Diastolic BP
Time frame: From baseline to 6 months
Population: PPS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Office Diastolic BP | 12.6 mmHg | Standard Deviation 15.6 |
| Conventional Renal Denervation | Changes of Office Diastolic BP | 10.4 mmHg | Standard Deviation 12.1 |
p-value: 0.59t-test, 2 sided
Secondary
Changes of Office Systolic BP
Time frame: From baseline to 12 months
Population: ITT analysis by Last Observation Carried Forward (LOCF) method in the subjects with the available data . (Six month data were used in 4 late (\>6 months) dropouts and also in 1 patient without 12 month' ABPM, 1 month data were used in 2 early (\<6 months) dropouts. One patient had no post procedure data at all and was excluded from analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Office Systolic BP | 12.8 mmHg | Standard Deviation 15.7 |
| Conventional Renal Denervation | Changes of Office Systolic BP | 10.8 mmHg | Standard Deviation 18.8 |
p-value: 0.66t-test, 2 sided
Secondary
Changes of Office Systolic BP
Time frame: From baseline to 6 months
Population: PPS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Office Systolic BP | 26.1 mmHg | Standard Deviation 226.8 |
| Conventional Renal Denervation | Changes of Office Systolic BP | 21.2 mmHg | Standard Deviation 23.3 |
p-value: 0.49t-test, 2 sided
Secondary
Changes of Serum Creatinine
Time frame: From baseline to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Serum Creatinine | 2.0 μmol/l | Standard Deviation 13.4 |
| Conventional Renal Denervation | Changes of Serum Creatinine | 2.3 μmol/l | Standard Deviation 12.5 |
p-value: 0.2795% CI: [-11.9, 3.4]t-test, 2 sided
Secondary
Changes of Serum Creatinine
Time frame: From baseline to 12 months
Population: Intention-to-treat (ITT) analysis by Last Observation Carried Forward (LOCF) method. (Six month data were used in 4 late (\>6 months) dropouts and also in 1 patient without 12 month' ABPM, 1 month data were used in 2 early (\<6 months) dropouts. One patient had no post procedure data at all and was excluded from analysis)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Distal Renal Denervation | Changes of Serum Creatinine | 9.8 μmol/l | Standard Error 19.7 |
| Conventional Renal Denervation | Changes of Serum Creatinine | 2.0 μmol/l | Standard Error 19.8 |
p-value: 0.1795% CI: [-3.7, 19.3]t-test, 2 sided
Secondary
Number of Adverse Events
Time frame: From baseline to 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Distal Renal Denervation | Number of Adverse Events | 1 adverse event |
| Conventional Renal Denervation | Number of Adverse Events | 0 adverse event |
Secondary
Number of Adverse Events
Time frame: From baseline to 12 months
Population: A baseline population except those who refused to continue in the study before final assessment and thereby whose status was unknown at 12 months follow up (5 in the distal denervation arm and 3 patients in conventional denervation arm).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Distal Renal Denervation | Number of Adverse Events | 4 adverse event |
| Conventional Renal Denervation | Number of Adverse Events | 2 adverse event |