Atrial Fibrillation, Hypertension
Conditions
Brief summary
The purpose of this clinical study is to evaluate the feasibility of performing both renal nerve denervation and pulmonary vein isolation on the same patient with the intent of characterizing both safety and effectiveness in a paroxysmal and persistent atrial fibrillation population with hypertension. To assess safety, the study will measure the occurrence of a composite safety endpoint and, to assess effectiveness, the study will measure freedom of chronic treatment failure through a minimum of six months of follow-up.
Interventions
DEVICESymplicity Spyral™ Multi-Electrode Renal Denervation Catheter
DEVICEArctic Front Advance™ Cardiac Cryoablation System
Sponsors
Medtronic Vascular
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Drug refractory recurrent symptomatic paroxysmal or persistent atrial fibrillation * Office-based systolic blood pressure of ≥140 mm Hg based despite treatment with 1 or more antihypertensive medications * Age 18 years to 80 years old. Key
Exclusion criteria
* Renal artery anatomy that is ineligible for treatment including: Lacks at least one renal artery for each kidney with ≥3 mm diameter and minimum treatable length per the Spyral Instructions for Use, Renal artery stenosis (\>50%) or renal artery aneurysm in either renal artery, A history of prior renal artery intervention including balloon angioplasty or stenting, Renal artery which contain calcification which does not allow at least four radio frequency ablations to be delivered , Diffuse fibromuscular dysplasia (FMD) or FMD which does not allow at least four radio frequency ablations to be delivered; FMD defined as visible beading of the artery on angiography , Unilateral kidney. * Estimated Glomerular Filtration Rate of \<30 mL/min/1.73m2. * Pregnant, nursing or planning to be pregnant. (Female participants of childbearing potential must have a negative serum or urine human chorionic gonadotropin (hCG) pregnancy test prior to angiography). * Currently enrolled or plans to participate in a potentially confounding drug or device trial during the course of this study. Co-enrollment in concurrent studies is allowed when documented pre-approval is obtained from the Medtronic study manager.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects in Each Arm That Experience Safety Composite Events | Up to one or six months post procedure depending on the event | Characterize the rate of safety composite events, (End stage renal disease, Death, Significant Embolic Event, Renal Artery Perforation or Dissection Requiring Intervention, Vascular Complications, Hospitalization for Hypertensive Crisis, New Renal Artery Stenosis, Cardiac Damage, Pulmonary Vein Stenosis, Atrio-Esophageal Fistula, Arrhythmia, Persistent Phrenic Nerve Palsy), within each of the two study arms and also characterize the difference in the rates between study arms. Each event in the composite has its own time frame, either one month or six months post procedure. |
| Proportion of Patients With Chronic Treatment Success | Minimum of six months | Chronic treatment success is freedom from chronic treatment failure. Chronic treatment failure is defined as the occurrence of either a documented episode of AF lasting 2 or more minutes (as measured by an implantable loop recorder) or an intervention for AF. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Procedural Measures | Procedure | Elapsed fluoroscopy time and cryocatheter procedure time between study arms. Renal Denervation Procedure Time and Total Procedural Time will be reported only for the Cryoablation and Renal Denervation group. |
| Proportion of Participants With Symptoms at 6 Months Between Study Arms | 6 months | The endpoints for this objective are presence of the following arrhythmic symptoms as recorded at the 6-month visit through discussion with the patient at the time of the visit: * Dizziness * Palpitations * Rapid heart beat * Dyspnea * Fatigue * Syncope * Other |
| Change in Office Systolic and Diastolic Blood Pressure at 6 Months From Baseline | 6 months | Compare the difference of office systolic and diastolic blood pressure at 6 months and baseline between study arms. |
| Percent of Time in AF Burden Over All Follow-up Occurring After the Blanking Period | 91 days after the cryoablation procedure date until the last Reveal LINQ device data date. | Compare the Percent of time in AF burden over all follow-up occurring after the blanking period between study arms. |
| Rate of Chronic Treatment Success (Primary Effectiveness Endpoint) for Subjects Off of Class I and III Anti-arrhythmic Drugs Following the Blanking Period. | 6 months | Compare the rate of chronic treatment success (primary effectiveness endpoint) between study arms for subjects off of Class I and III anti-arrhythmic drugs following the blanking period. |
| Difference in Heart Rate at 6 Months and Baseline | 6 months | Compare the difference in heart rate using the 6 month follow-up measurement and baseline visit measurement. These values will then be compared between study arms. |
Countries
Germany, United States
Participant flow
Recruitment details
The first subject was enrolled on February 6, 2015 and the last subject was enrolled on September 9, 2020
Pre-assignment details
28 subjects were exited prior to randomization for not meeting study eligibility criteria. Of the 74 randomized subjects, 3 in the PVI+RDN group were not treated and 1 in the Control group (PVI only) were not treated.
Participants by arm
| Arm | Count |
|---|---|
| Cryoablation Only Pulmonary vein isolation
Arctic Front Advance™ Cardiac Cryoablation System | 36 |
| Cryoablation and Renal Nerve Denervation Pulmonary vein isolation plus renal nerve denervation
Symplicity Spyral™ Multi-Electrode Renal Denervation Catheter
Arctic Front Advance™ Cardiac Cryoablation System | 34 |
| Total | 70 |
Baseline characteristics
| Characteristic | Cryoablation Only | Cryoablation and Renal Nerve Denervation | Total |
|---|---|---|---|
| Age, Continuous | 65.1 years STANDARD_DEVIATION 7.8 | 65.8 years STANDARD_DEVIATION 7.8 | 65.4 years STANDARD_DEVIATION 7.7 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not reportable per local laws or regulations | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Subject/Physician Chose Not to Provide Information | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 27 Participants | 28 Participants | 55 Participants |
| Region of Enrollment Germany | 8 participants | 10 participants | 18 participants |
| Region of Enrollment United States | 28 participants | 24 participants | 52 participants |
| Sex: Female, Male Female | 13 Participants | 18 Participants | 31 Participants |
| Sex: Female, Male Male | 23 Participants | 16 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 36 | 0 / 34 |
| other Total, other adverse events | 22 / 36 | 24 / 34 |
| serious Total, serious adverse events | 17 / 36 | 20 / 34 |
Outcome results
Primary
Proportion of Patients With Chronic Treatment Success
Chronic treatment success is freedom from chronic treatment failure. Chronic treatment failure is defined as the occurrence of either a documented episode of AF lasting 2 or more minutes (as measured by an implantable loop recorder) or an intervention for AF.
Time frame: Minimum of six months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cryoablation Only | Proportion of Patients With Chronic Treatment Success | 11 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Patients With Chronic Treatment Success | 10 Participants |
p-value: 0.7348Log Rank
Primary
Proportion of Subjects in Each Arm That Experience Safety Composite Events
Characterize the rate of safety composite events, (End stage renal disease, Death, Significant Embolic Event, Renal Artery Perforation or Dissection Requiring Intervention, Vascular Complications, Hospitalization for Hypertensive Crisis, New Renal Artery Stenosis, Cardiac Damage, Pulmonary Vein Stenosis, Atrio-Esophageal Fistula, Arrhythmia, Persistent Phrenic Nerve Palsy), within each of the two study arms and also characterize the difference in the rates between study arms. Each event in the composite has its own time frame, either one month or six months post procedure.
Time frame: Up to one or six months post procedure depending on the event
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cryoablation Only | Proportion of Subjects in Each Arm That Experience Safety Composite Events | 1 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Subjects in Each Arm That Experience Safety Composite Events | 3 Participants |
p-value: 0.28Log Rank
Secondary
Change in Office Systolic and Diastolic Blood Pressure at 6 Months From Baseline
Compare the difference of office systolic and diastolic blood pressure at 6 months and baseline between study arms.
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cryoablation Only | Change in Office Systolic and Diastolic Blood Pressure at 6 Months From Baseline | Office Systolic BP | -11.6 mmHg | Standard Deviation 16.7 |
| Cryoablation Only | Change in Office Systolic and Diastolic Blood Pressure at 6 Months From Baseline | Office Diastolic BP | -5.6 mmHg | Standard Deviation 11.6 |
| Cryoablation and Renal Nerve Denervation | Change in Office Systolic and Diastolic Blood Pressure at 6 Months From Baseline | Office Systolic BP | -13.3 mmHg | Standard Deviation 16.8 |
| Cryoablation and Renal Nerve Denervation | Change in Office Systolic and Diastolic Blood Pressure at 6 Months From Baseline | Office Diastolic BP | -5.8 mmHg | Standard Deviation 10 |
Secondary
Difference in Heart Rate at 6 Months and Baseline
Compare the difference in heart rate using the 6 month follow-up measurement and baseline visit measurement. These values will then be compared between study arms.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cryoablation Only | Difference in Heart Rate at 6 Months and Baseline | -1.9 beats per minute | Standard Deviation 17.3 |
| Cryoablation and Renal Nerve Denervation | Difference in Heart Rate at 6 Months and Baseline | 1.8 beats per minute | Standard Deviation 16.5 |
Secondary
Percent of Time in AF Burden Over All Follow-up Occurring After the Blanking Period
Compare the Percent of time in AF burden over all follow-up occurring after the blanking period between study arms.
Time frame: 91 days after the cryoablation procedure date until the last Reveal LINQ device data date.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cryoablation Only | Percent of Time in AF Burden Over All Follow-up Occurring After the Blanking Period | 2.78 Percent of time | Standard Deviation 5.96 |
| Cryoablation and Renal Nerve Denervation | Percent of Time in AF Burden Over All Follow-up Occurring After the Blanking Period | 1.75 Percent of time | Standard Deviation 5.35 |
Secondary
Procedural Measures
Elapsed fluoroscopy time and cryocatheter procedure time between study arms. Renal Denervation Procedure Time and Total Procedural Time will be reported only for the Cryoablation and Renal Denervation group.
Time frame: Procedure
Population: The analysis population for Renal Denervation Procedure and Total Procedure Time does not include participants from the Cryoablation only group since they did not receive the Renal Artery Denervation Procedure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cryoablation Only | Procedural Measures | Elapsed Fluoroscopy time | 25.4 minutes | Standard Deviation 18.9 |
| Cryoablation Only | Procedural Measures | Cryocatheter Procedure Time | 66.2 minutes | Standard Deviation 25.6 |
| Cryoablation and Renal Nerve Denervation | Procedural Measures | Elapsed Fluoroscopy time | 34 minutes | Standard Deviation 19.8 |
| Cryoablation and Renal Nerve Denervation | Procedural Measures | Cryocatheter Procedure Time | 68.3 minutes | Standard Deviation 27.3 |
| Cryoablation and Renal Nerve Denervation | Procedural Measures | Renal Artery Denervation Procedure Time | 51.2 minutes | Standard Deviation 16.4 |
| Cryoablation and Renal Nerve Denervation | Procedural Measures | Total Procedure Time | 119.5 minutes | Standard Deviation 35.3 |
Secondary
Proportion of Participants With Symptoms at 6 Months Between Study Arms
The endpoints for this objective are presence of the following arrhythmic symptoms as recorded at the 6-month visit through discussion with the patient at the time of the visit: * Dizziness * Palpitations * Rapid heart beat * Dyspnea * Fatigue * Syncope * Other
Time frame: 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Dizziness at Baseline | 17 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Dizziness at 6 months | 6 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Palpitations at Baseline | 29 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Palpitations at 6 months | 11 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Rapid Heart Beat at Baseline | 19 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Rapid Heart Beat at 6 months | 4 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Dyspnea at Baseline | 25 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Dyspnea at 6 months | 6 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Fatigue at Baseline | 16 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Fatigue at 6 months | 6 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Syncope at Baseline | 1 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Syncope at 6 months | 0 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Other at Baseline | 13 Participants |
| Cryoablation Only | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Other at 6 months | 2 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Syncope at Baseline | 1 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Dizziness at Baseline | 11 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Dyspnea at 6 months | 7 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Dizziness at 6 months | 4 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Other at Baseline | 10 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Palpitations at Baseline | 27 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Fatigue at Baseline | 20 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Palpitations at 6 months | 9 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Syncope at 6 months | 0 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Rapid Heart Beat at Baseline | 18 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Fatigue at 6 months | 8 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Rapid Heart Beat at 6 months | 6 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Other at 6 months | 2 Participants |
| Cryoablation and Renal Nerve Denervation | Proportion of Participants With Symptoms at 6 Months Between Study Arms | Dyspnea at Baseline | 21 Participants |
Secondary
Rate of Chronic Treatment Success (Primary Effectiveness Endpoint) for Subjects Off of Class I and III Anti-arrhythmic Drugs Following the Blanking Period.
Compare the rate of chronic treatment success (primary effectiveness endpoint) between study arms for subjects off of Class I and III anti-arrhythmic drugs following the blanking period.
Time frame: 6 months
Population: If a subject has not used Class I or III anti-arrhythmic drugs at all following the blanking period, all of their follow-up will be used for this analysis. If a subject has used either Class I or Class III anti-arrhythmic drugs after the blanking period, they will be excluded for this analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cryoablation Only | Rate of Chronic Treatment Success (Primary Effectiveness Endpoint) for Subjects Off of Class I and III Anti-arrhythmic Drugs Following the Blanking Period. | Treatment Failure | 13 Participants |
| Cryoablation Only | Rate of Chronic Treatment Success (Primary Effectiveness Endpoint) for Subjects Off of Class I and III Anti-arrhythmic Drugs Following the Blanking Period. | No Treatment Failure | 7 Participants |
| Cryoablation and Renal Nerve Denervation | Rate of Chronic Treatment Success (Primary Effectiveness Endpoint) for Subjects Off of Class I and III Anti-arrhythmic Drugs Following the Blanking Period. | Treatment Failure | 16 Participants |
| Cryoablation and Renal Nerve Denervation | Rate of Chronic Treatment Success (Primary Effectiveness Endpoint) for Subjects Off of Class I and III Anti-arrhythmic Drugs Following the Blanking Period. | No Treatment Failure | 8 Participants |
Post Hoc
Daily Atrial Arrhythmia Burden From Baseline to End of ILR Recording for Patients Who Had a Mean Burden of Greater Than or Equal to 1 Hour Per Day on the Days They Experienced Atrial Arrhythmia(s)
Calculate the daily atrial arrhythmia burden in hours from baseline to end of the ILR recording. The patients who had a mean burden of 1 or more hours per day on the days they experienced atrial arrhythmias are included in the analysis. From these patients, it is then determined the mean daily atrial arrhythmia burden between groups.
Time frame: Baseline till end of recording of implantable loop recorder
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cryoablation Only | Daily Atrial Arrhythmia Burden From Baseline to End of ILR Recording for Patients Who Had a Mean Burden of Greater Than or Equal to 1 Hour Per Day on the Days They Experienced Atrial Arrhythmia(s) | 9.2 hours | Standard Deviation 6 |
| Cryoablation and Renal Nerve Denervation | Daily Atrial Arrhythmia Burden From Baseline to End of ILR Recording for Patients Who Had a Mean Burden of Greater Than or Equal to 1 Hour Per Day on the Days They Experienced Atrial Arrhythmia(s) | 4.1 hours | Standard Deviation 3.5 |
Post Hoc
Number of Patients Who Discontinued Class I/III Anti-arrhythmic Drugs
Compare the number of patients who discontinued Class I/III anti-arrhythmic drugs between groups
Time frame: Baseline till end of follow-up (varies per patient)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cryoablation Only | Number of Patients Who Discontinued Class I/III Anti-arrhythmic Drugs | 3 Participants |
| Cryoablation and Renal Nerve Denervation | Number of Patients Who Discontinued Class I/III Anti-arrhythmic Drugs | 9 Participants |