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| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P130021 S002/ PAS001 |
| Date Original Protocol Accepted |
06/12/2014
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| Date Current Protocol Accepted |
05/09/2017
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| Study Name |
Continued f/u of the premarket cohorts
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| Device Name |
MEDTRONIC COREVALVE SYSTEM
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| General Study Protocol Parameters |
| Study Design |
Prospective Cohort Study
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| Data Source |
New Data Collection
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| Comparison Group |
Concurrent Control
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| Analysis Type |
Descriptive
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| Study Population |
Transit. Adolescent B (as adults) : 18-21 yrs,
Adult: >21
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| Detailed Study Protocol Parameters |
| Study Objectives |
Extended follow-up study of all available subjects that were enrolled in the Medtronic CoreValve® U.S. Pivotal Trial and Continued Access Study who received the Medtronic CoreValve® System (MCS) or underwent surgical aortic valve replacement (SAVR).
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| Study Population |
High risk and extreme risk subjects currently consented to and enrolled in the Medtronic U.S. Pivotal Trial and Continued Access Study who received the MCS or underwent SAVR.
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| Sample Size |
All available subjects enrolled in the US Pivotal Trial, 394 subjects randomized to transcatheter aortic valve replacement (TAVR) and 401 subjects randomized to surgical aortic valve replacement (SAVR), and 76 roll-in subjects in all sites (up to 45) and approximately 2800 CAP subjects.
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| Key Study Endpoints |
The primary endpoint of all-cause mortality at 12 months in High Risk subjects is non-inferior to surgical aortic valve replacement (SAVR), has been met. Clinical outcomes will be characterized annually through 5 years.
The secondary endpoints through 12 months have been evaluated. The following secondary endpoints will characterize clinical outcomes annually through 5 years:
A. Major Adverse Cardiovascular and Cerebrovascular Event (MACCE) event rates via Kaplan-Meier. MACCE is defined as a composite of:
¿ all-cause death
¿ myocardial infarction (MI)
¿ all stroke, and
¿ reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve)
2. The occurrence of individual MACCE components event rates via Kaplan-Meier
3. Major Adverse Events (MAE) event rates via Kaplan-Meier
4. Conduction disturbance requiring permanent pacemaker implantation event rates via Kaplan-Meier
5. Change in NYHA class
6. Quality of Life (QoL) change using the following measures:
¿ Kansas City Cardiomyopathy Questionnaire (KCCQ)
¿ SF 12, and
¿ EuroQoL
7. Echocardiographic assessment of valve performance using the following measures:
¿ transvalvular mean gradient
¿ effective orifice area
¿ degree of aortic valve regurgitation (transvalvular and paravalvular)
8. Aortic valve disease hospitalization event rates via Kaplan-Meier
9. Cardiovascular deaths and valve-related deaths event rates via Kaplan-Meier
10.Strokes (of any severity) and TIAs event rates via Kaplan-Meier
11.Evidence of prosthetic valve dysfunction
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| Follow-up Visits and Length of Follow-up |
Annually through 5 years
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| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
Pivotal Extreme Risk Cohort: 656
CAP Extreme Risk Cohort: 1,658
Pivotal High Risk Cohort: 797
CAP High Risk Cohort: 1,119
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| Actual Number of Sites Enrolled |
Pivotal Extreme Risk Cohort: 41 study sites
CAP Extreme Risk Cohort: 45 study sites
Pivotal High Risk Cohort: 45 study sites
CAP High Risk Cohort: 45 study sites
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| Patient Follow-up Rate |
Pivotal Extreme Risk Cohort: 96.2% at 5 years (152/158)
CAP Extreme Risk Cohort: 91.6% at 5 years (1488/1624)
Pivotal High Risk Cohort: 92.9% at 5 years in TAVR ITT subjects (367/395); 77.9% at 5 years in SAVR ITT subjects (313/402)
CAP High Risk Cohort: 89.6% at 5 years (993/1108)
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| Final Safety Findings |
Pivotal Extreme Risk Cohort: The Kaplan Meier (K-M) rate of all-cause mortality or major stroke in the extreme risk (ER) Pivotal Cohort at 60 months was 71.7% in Iliofemoral subjects and 72.6% in combined group. The KM rate for all-cause mortality at 60 months was 70.9% in Iliofemoral subjects and 71.6% in combine group. The KM rate of cardiovascular mortality at 60 months was 55.0% in Iliofemoral group and 55.8% in combine group.
CAP Extreme Risk Cohort: The Kaplan Meier (K-M) rate for all-cause mortality at 60 months was 69.1%.
Pivotal High Risk Cohort: The Kaplan-Meier (K-M) rate for all-cause mortality was 55.1% and 55.3% at 60 months for TAVR subjects and SAVR subjects respectively. The K-M rate of all stroke (major and minor) at 60 months was 17.5% in the TAVR cohort and 21.0% in the SAVR cohort.
CAP High Risk Cohort: The Kaplan Meier (K-M) rate for all-cause mortality at 60 months was 60.3%.
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| Final Effect Findings |
Pivotal Extreme Risk Cohort: The mean change in NYHA class at 60 months compared to baseline remained statistically significant with a mean reduction of -1.5 + 0.8 in Iliofemoral subjects and -1.4+0.8 in combine group (p<0.0001). The change in KCCQ overall summary score at 60 months compared to baseline remained statistically significant with a mean change of 21.2 +/- 27.9 in Iliofemoral subjects and 21.2+27.0 in combine group (p<0.0001). The EOAs values remained stable throughout the follow-up visits and the EOA mean for all sizes was reported 1.83+0.64 cm2 at 60 months
CAP Extreme Risk Cohort: The mean change in NYHA class at 60 months compared to baseline is statistically significant with a mean reduction of -1.3 + 0.8 (p<0.0001). The change in KCCQ overall summary score at 60 months compared to baseline is statistically significant with a mean change of 24.0 + 28.8 (p<0.0001). The low post-procedure mean gradients remained stable through the subsequent follow-up visits and mean gradient 7.03 +/- 4.02 mmHg (n=260) was observed for the Extreme Risk cohort at 60 months. EOA values remained stable throughout the follow-up visits and a mean EOA of 1.92 +/- 0.61 cm2 was reported for the ER group (n=285) at 60 months.
Pivotal High Risk Cohort: The mean change in NYHA class at 60 months compared to baseline is statistically significant with a mean reduction of -1.3 + 0.9 (p<0.0001) for TAVR subjects and of -1.3 + 0.8 (p<0.0001) for SAVR. The change in KCCQ overall summary score at 60 months compared to baseline is statistically significant with a mean change of 15.2 + 28.3 (p<0.0001) for TAVR and 15.8 + 25.4 for SAVR (p<0.0001). A mean gradient of 7.07 +/- 3.55 mmHg was observed for the TAVR subjects at 60 months (N=114) and 10.93 + /- 5.71 mmHg (N=90) was observed in the SAVR group at the 60-month follow-up (p<0.0001 vs TAVR). EOA values remained stable throughout the follow-up visits and a mean EOA of 1.92 +/- 0.58 cm2 was reported for the TAVR group (N=101) and 1.66 +/- 0.61 cm2 for the SAVR group (N=86) at 60 months (p=0.003 vs TAVR).
CAP High Risk Cohort: The mean change in NYHA class at 60 months compared to baseline is statistically significant with a mean reduction of -1.3 + 0.8 (p<0.0001). The change in KCCQ overall summary score at 60 months compared to baseline is statistically significant with a mean change of 21.0 + 26.1 (p<0.0001). The low post-procedure mean gradients remained stable through the subsequent follow-up visits and mean gradient 7.14 +/- 4.25 mmHg (n=260) was observed for the High Risk cohort at 60 months. EOA values remained stable throughout the follow-up visits and a mean EOA of 1.90 +/- 0.58 cm2 was reported for the HR group (n=240) at 60 months.
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| Study Strengths & Weaknesses |
Pivotal Extreme Risk Cohort: The ER Pivotal trial compliance rate was high (i.e., 96.7%) at 5 years. The ER Pivotal trial met the primary
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endpoints and provided long term data. However, the KM rate of all-cause mortality was high (i.e., 71.6%) in the combined group at 5 years. These patients tended to have a worse baseline health condition with high STS score of 10.4 +/- 5.6% (combined group) and this could have contributed to the high all-cause mortality. Given that all-cause mortality is an evaluable endpoint for the study, this data was captured. Thus, patient exit through death is likely to have less impact on the validity of the study results.
Pivotal High Risk Cohort: For the HR Pivotal cohort, improvements in hemodynamic and functional performance were generally preserved through 5 years as evidenced by echocardiographic results, NYHA classification and overall KCCQ score. The 5 year follow-up was lower for SAVR than TAVR in both the ITT and AT cohorts. 77.9% of the SAVR ITT cohort had completed follow-up as compared to 92.9% of the TAVR ITT cohort. 85.8% of the SAVR AT cohort had completed follow-up as compared to 93.4% of the TAVR AT cohort. This raises the possibility of non-random missingness which could result in biased longer-term data.
CAP Extreme Risk Cohort & CAP High Risk Cohort:
The unadjusted mortality rates (i.e. mortality rates that do not take into account known risk factors for death such as subject’s age or comorbidities at baseline) for both the ER and HR cohorts, over the study duration, are in line with the unadjusted mortality rates previously reported for other studied CoreValve TAVR patient populations with multiple comorbidities and/or risk factors. The follow-up rate for potentially eligible subjects (not dead and in visit window) was lower than ideal at the five-year visits for both the ER and HR cohorts (75% for both). However, the overall follow-up rate for subjects with attempted procedures is high when known deaths are included as followed (91.6% for ER and 89.6% for HR). Also, data completion for key assessments such as echocardiograph are lower than ideal for the longer-term follow-up visits. Because there was loss to follow-up and missing assessments, the potential for selection bias due to systematic attrition or systematically missing assessments cannot be ruled out.
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| Recommendations for Labeling Changes |
Pivotal Extreme Risk Cohort & CAP Extreme Risk Cohorts: The CoreValve System used for this study is no longer marketed – replaced by the EvolutR and then the EvolutPro. No labeling changes are recommended.
Pivotal High Risk Cohort & CAP High Risk Cohorts: Complete longer-term follow-up data for the Pivotal High Risk and Continued Access Study High-Risk cohorts warrants inclusion into the labeling for the device and should be informative to clinicians and patients regarding the longer-term benefit risk profile for the device.
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