Neuroprotection in Patients Undergoing Aortic Valve Replacement

Neuroprotection In Patients Undergoing Aortic Valve Replacement

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02389894

Enrollment

383

Registered

2015-03-17

Start date

2015-03-31

Completion date

2017-01-31

Last updated

2019-04-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Aortic Stenosis, Brain Infarction, Cerebrovascular Accident, Stroke

Keywords

Embolic Protection Device, Stroke, Brain Infarction, atheroma, Aortic Valve Replacement

Brief summary

To evaluate the efficacy and safety of embolic protection devices to reduce ischemic brain injury in patients undergoing surgical aortic valve replacement (AVR).

Detailed description

This is a multicenter randomized trial in which patients diagnosed with calcific aortic stenosis (AS) with planned AVR will be randomized to 1) the treatment arm of the Edwards Life Science filter and cannula or the filter as a stand alone with any cannula or 2) to the treatment arm of the CardioGard cannula versus 3) standard care in a 1:1:1 ratio.

Interventions

DEVICEEmbol-X Embolic Protection Device

per the manufacturer's instructions for use (IFU).

DEVICECardioGard Cannula

CardioGard Cannula, per the manufacturer's instructions for use (IFU).

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

SINGLE (Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

60 Years to No maximum

Healthy volunteers

Inclusion criteria

* Age ≥ 60 years * Planned and scheduled surgical aortic valve replacement via a full or minimal-access sternotomy (using central aortic perfusion cannulae) for calcific aortic stenosis with a legally marketed valve * No evidence of neurological impairment as defined by a NIHSS ≤1 and modified Rankin scale (mRS) ≤ 2 within 7 days prior to randomization * Ability to provide informed consent and comply with the protocol

Exclusion criteria

* Contraindication to legally marketed embolic protection devices (e.g. aneurysm of the ascending aorta, aortic trauma, porcelain aorta, known sensitivity to heparin) * History of clinical stroke within 3 months prior to randomization * Cardiac catheterization within 3 days of the planned aortic valve replacement * Cerebral and or aortic arch arteriography or interventions within 3 days of the planned aortic valve replacement * Active endocarditis at time of randomization * Anticipated inability to tolerate or contraindication for MRI (e.g., known intolerance of MRI, permanent pacemaker at baseline or expected implantation of a permanent pacemaker) * Any other concomitant aortic procedure such as root replacement * Concomitant surgical procedures other than CABG, mitral annuloplasty, left atrial appendage (LAA) excision or exclusion, atrial septal defect (ASD) closure or patent foramen ovale (PFO) closure * Clinical signs of cardiogenic shock or treatment with IV inotropic therapy prior to randomization * Concurrent participation in an interventional (drug or device) trial

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Freedom From Clinical or Radiographic Central Nervous System (CNS) Infarction	up to 10 days post procedure	freedom from CNS infarction, defined as brain, spinal cord, or retinal cell death attributable to ischemia based on neuropathological, neuroimaging, or clinical evidence of permanent injury based on symptoms persisting \> 24 hours, with overt symptoms or no known symptoms. All patients will be assessed by 1.5 T (3.0 T is acceptable if 1.5 T not available) Diffusion-weighted imaging (DWI) at 7 (± 3) days post procedure for presence of brain lesions and to measure the number and volume of any present lesions.

Secondary

Measure	Time frame	Description
Number of Patients With Clinically Apparent Stroke at 7 Days	at 7 days	The number of patients who experience a clinically apparent stroke by 7 days post-op
Presence of Radiographic Infarcts	up to 10 days	The proportion of patients with radiographic infarcts on day 7 (+/-3 days) MRI. Presences of radiographic infarcts were measured using diffusion-weighted 1.5 or 3T MRI scanners
Total Infarct Volume	Day 7	Total infarct volume measured on day 7 dwMRI.
Decline in Overall Neurocognition	baseline and 90 days	Decline in neurocognitive function at 90 days as compared to baseline. Decline defined as the number of patients whose Z score (computed relative to the study population at baseline, adjusting for age, education and sex) at day 90 had decreased by 0.5 SD relative to the baseline score.
Decline in Neurocognitive Function in the Verbal Memory Domain at 90 Days	baseline and 90 days	Decline in neurocognitive function in the verbal memory domain at 90 days as compared to baseline. Decline defined as the number of patients whose Z score (computed relative to the study population at baseline, adjusting for age, education and sex) at day 90 had decreased by 0.5 SD relative to the baseline score.
Decline in Neurocognitive Function in the Visual Memory Domain at 90 Days	baseline and 90 days	Decline in neurocognitive function in the visual memory domain at 90 days as compared to baseline. Decline defined as the number of patients whose Z score (computed relative to the study population at baseline, adjusting for age, education and sex) at day 90 had decreased by 0.5 SD relative to the baseline score.
Decline in Neurocognitive Function in the Executive Function Domain at 90 Day	baseline and 90 days	Decline in neurocognitive function in the executive function domain at 90 days as compared to baseline. Decline defined as the number of patients whose Z score (computed relative to the study population at baseline, adjusting for age, education and sex) at day 90 had decreased by 0.5 SD relative to the baseline score.
Decline in Neurocognitive Function in the Visuospatial/Constructional Praxis Domain at 90 Days	baseline and 90 days	Decline in neurocognitive function in the visuospatial/constructional praxis domain at 90 days as compared to baseline. Decline defined as the number of patients whose Z score (computed relative to the study population at baseline, adjusting for age, education and sex) at day 90 had decreased by 0.5 SD relative to the baseline score.
Decline in Neurocognitive Function in the Auditory-Verbal Simple Attention Domain at 90 Days	baseline and 90 days	Decline in neurocognitive function in the Auditory-Verbal Simple attention domain at 90 days as compared to baseline. Decline defined as the number of patients whose Z score (computed relative to the study population at baseline, adjusting for age, education and sex) at day 90 had decreased by 0.5 SD relative to the baseline score.
Number of Participants With a Composite Endpoint of Mortality, Clinical Stroke, and Acute Kidney Injury	up to 30 days	The number of patients who have had a clinical ischemic stroke, acute kidney injury (AKI), or death within 30 days of surgery.
Modified Rankin Scale >2 at 90 Days	90 days	The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms. 1. \- No significant disability. Able to carry out all usual activities, despite some symptoms. 2. \- Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3. \- Moderate disability. Requires some help, but able to walk unassisted. 4. \- Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5. \- Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6. \- Dead.
Barthel Index <= 80	90 days	An overall score has full range from 0 to 100, with higher scores indicating greater independence.
Number of Participants With Confusion Assessment Method (CAM) Delirium Assessment at 7 Days	7 days	—
Mortality by 90 Days	up to 90 days	Incidence of all-cause mortality
Length of Stay for Index Hospitalization	up to 90 days	—
Hospital Readmissions	up to 90 days	Rate of hospital readmissions
Quality of Life - Physical Health Composite	at 90 days	Quality of Life - Physical Health Composite Assessed by Short Form-12 (SF-12). Score ranking from 0 (worst health) to 100 (best health) calculated as the weighted sum of the questions. health scores then transformed into a t-score on the assumption that each question carries equal weight and were standardized to have mean of 50 and standard deviation of 10.
Quality of Life - Mental Health Composite	at 90 days	Quality of life - Mental health composite Assessed by Short Form-12 (SF-12). Score ranking from 0 (worst health) to 100 (best health) calculated as the weighted sum of the questions. health scores then transformed into a t-score on the assumption that each question carries equal weight and were standardized to have mean of 50 and standard deviation of 10.
Number of Participants With Emboli Captured	day 1	Assessed by the presence of any debris captured in filter of embolic protection device
Decline in Neurocognitive Function in the Visuomotor/Information Processing Speed Domain at 90 Days	baseline and 90 days	Decline in neurocognitive function in the Visuomotor/Information Processing Speed domain at 90 days as compared to baseline. Decline defined as the number of patients whose Z score (computed relative to the study population at baseline, adjusting for age, education and sex) at day 90 had decreased by 0.5 SD relative to the baseline score.

Countries

Canada, United States

Participant flow

Participants by arm

Arm	Count
Embol-X Embolic Protection Device The surgeon may use either the EMBOL-X® Access Device/Aortic Cannula or a standard cannula with the EMBOL-X® filter deployed through a separate introducer sheath. Embol-X Embolic Protection Device: per the manufacturer's instructions for use (IFU).	133
CardioGard Cannula The Cardiogard embolic protection device is a curved tip 24-French aortic perfusion cannula. CardioGard Cannula: CardioGard Cannula, per the manufacturer's instructions for use (IFU).	118
Standard Cannula Patients in this arm will receive the standard of care surgical procedure using a cannula of the surgeon's choosing.	132
Total	383

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Death	4	5	3
Overall Study	Lost to Follow-up	2	1	1
Overall Study	Withdrawal by Subject	2	4	5

Baseline characteristics

Characteristic	Embol-X Embolic Protection Device	Total	Standard Cannula	CardioGard Cannula
Age, Continuous	73.6 years STANDARD_DEVIATION 6.6	73.9 years STANDARD_DEVIATION 6.7	73.6 years STANDARD_DEVIATION 6.7	74.6 years STANDARD_DEVIATION 6.8
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	17 Participants	8 Participants	5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	127 Participants	358 Participants	121 Participants	110 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants	8 Participants	3 Participants	3 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	2 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	5 Participants	5 Participants	0 Participants
Race (NIH/OMB) Black or African American	6 Participants	19 Participants	6 Participants	7 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	5 Participants	3 Participants	2 Participants
Race (NIH/OMB) White	126 Participants	352 Participants	118 Participants	108 Participants
Region of Enrollment Canada	19 participants	57 participants	19 participants	19 participants
Region of Enrollment United States	114 participants	326 participants	113 participants	99 participants
Sex: Female, Male Female	52 Participants	147 Participants	46 Participants	49 Participants
Sex: Female, Male Male	81 Participants	236 Participants	86 Participants	69 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	4 / 133	5 / 118	3 / 132
other Total, other adverse events	45 / 133	47 / 118	43 / 132
serious Total, serious adverse events	72 / 133	53 / 118	54 / 132

Outcome results

Primary

Percentage of Participants With Freedom From Clinical or Radiographic Central Nervous System (CNS) Infarction

freedom from CNS infarction, defined as brain, spinal cord, or retinal cell death attributable to ischemia based on neuropathological, neuroimaging, or clinical evidence of permanent injury based on symptoms persisting \> 24 hours, with overt symptoms or no known symptoms. All patients will be assessed by 1.5 T (3.0 T is acceptable if 1.5 T not available) Diffusion-weighted imaging (DWI) at 7 (± 3) days post procedure for presence of brain lesions and to measure the number and volume of any present lesions.

Time frame: up to 10 days post procedure

Arm	Measure	Value (NUMBER)
Embol-X Embolic Protection Device	Percentage of Participants With Freedom From Clinical or Radiographic Central Nervous System (CNS) Infarction	74.4 percentage of participants
CardioGard Cannula	Percentage of Participants With Freedom From Clinical or Radiographic Central Nervous System (CNS) Infarction	68.0 percentage of participants
Standard Cannula	Percentage of Participants With Freedom From Clinical or Radiographic Central Nervous System (CNS) Infarction	67.6 percentage of participants

Comparison: A sample size of 165 patients in each group ensured that each comparison had a power of approximately 90% to detect a between-group difference of 17.5% from an assumed control rate of 50% in the incidence of postoperative CNS infarcts. A single interim analysis was prespecified and performed. Based on the recommendation of the DSMB, randomization but not follow-up was halted due to low conditional power of observing any between-group differences for the primary endpoint.p-value: 0.2295% CI: [-4.2, 17.9]Chi-squared

Secondary

Barthel Index <= 80

An overall score has full range from 0 to 100, with higher scores indicating greater independence.

Time frame: 90 days

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Embol-X Embolic Protection Device	Barthel Index <= 80	2 Participants
CardioGard Cannula	Barthel Index <= 80	2 Participants
Standard Cannula	Barthel Index <= 80	4 Participants

Secondary

Decline in Neurocognitive Function in the Auditory-Verbal Simple Attention Domain at 90 Days

Decline in neurocognitive function in the Auditory-Verbal Simple attention domain at 90 days as compared to baseline. Decline defined as the number of patients whose Z score (computed relative to the study population at baseline, adjusting for age, education and sex) at day 90 had decreased by 0.5 SD relative to the baseline score.