Acute Stroke, Endovascular Thrombectomy
Conditions
Keywords
Blood Pressure Control
Brief summary
The purpose of this study is to assess the safety of lowering blood pressure in acute stroke patients that are successfully treated with a mechanical thrombectomy procedure. The investogators will evaluate the hypothesis that lower blood pressure management strategies do not result in larger volume of stroke or worse 3-month clinical outcome in these patients.
Detailed description
Several thousand patients suffer from an ischemic stroke caused by an occlusion of a large blood vessel supplying the brain. Endovascular mechanical thrombectomy (EVT) has revolutionized management of this most devastating type of ischemic stroke by allowing removal of the occlusive clot. However, about half of the successfully EVT-treated patients (\ 85% of all treated patients) still remain disabled at 90 days. Early evidence suggests that patients with lower blood pressure (BP) after the thrombectomy procedure have better outcomes. However, safety of lowering BP in these patients has not been determined. The primary safety concern of lowering BP comes from the potential of compromising blood flow to the at risk area of the brain following the stroke. The purpose of this trial is to evaluate the safety of lower BP management strategies in patients who are successfully treated with endovascular treatment for ischemic stroke. The investigator will enroll 120 individuals who qualify and randomly assign them to one of the three systolic BP (SBP) targets: ≤180 mmHg, \<160 mmHg, and \<140 mmHg (40 patients in each group). Treatment will begin soon after the blood clot causing the stroke is removed, using anti-hypertensive medication given intravenously with a goal to lower and maintain the SBP below assigned target for 24 hrs. The scientists will assess the safety of lower BP targets (\<160 mmHg and \<140 mmHg) by quantifying the volume of stroke measured with an MRI scan obtained at 36+/-12 hours and participants' functional status at 90 days measured with a patient centered disability score. Participants will undergo the 36 +/-12-hour MRI scan as part of their routine clinical care and will not be asked to prolong their hospital stay for study purpose. A phone interview will take place to determine their functional status at 90-days. Enrollment of 120 patients will provide 80% power to detect a 10 cubic centimeter increase in stroke volume and a 0.10 decrease in utility-weighted modified Rankin score (a patient-centered disability score) for every 20 mmHg decrease in SBP. An interim analysis will be conducted after enrollment of 60 patients at which time the study may stop for safety concerns.
Interventions
DRUGNicardipine
In the event where SBP values are above the randomly assigned target, intravenous nicardipine will be initiated at 2.5 mg/hr to lower the SBP. If SBP is still not reduced to below assigned target after 15 minutes, nicardipine dose will be increased by 2.5 mg/hr every 15 minutes until the target SBP or a maximum dose of 15 mg/hr is reached.
DRUGLabetalol
If SBP is above target despite maximum nicardipine infusion for 30 minutes, 10-20 mg of intravenous labetalol will be added every 15 minutes.
DRUGHydralazine
If SBP remains unresponsive for 1 hr despite the use of maximum doses of nicardipine and labetalol, a Hydralazine will be added at the treating physician's discretion. Incidence of the latter scenario is anticipated to be exceedingly rare.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Vanderbilt University Medical Center
University of Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients (≥18 years) * Undergoing successful EVT (defined as modified Thrombolysis in Cerebral Ischemia Score, mTICI, ≥2b) for an occlusion in the anterior cerebral circulation large vessel (internal carotid artery and M1 or M2 segments of the middle cerebral artery). * Intervention will be initiated only for those with a successful recanalization (modified Thrombolysis in Cerebral Ischemia Score ≥ 2b). * Undergoing a baseline CT or MR perfusion study * Those with unsuccessful recanalization (mTICI 0-2a) will be not intervened upon.
Exclusion criteria
* Known heart failure with ejection fraction \<30% * Presence of a left ventricular assist device * Patients undergoing extracorporeal membrane oxygenation * Pregnancy * Enrollment in any other clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Final Infarct Volume | 36 (+/-12) hrs after treatment initiation | Infarct volume on diffusion-weighted MRI (or CT if MRI cannot be obtained) at 36 (+/-12) hrs after treatment initiation, adjusted for the baseline CT perfusion core infract volume. |
| Utility-weighted Modified Rankin Score | 90 days after treatment initiation | Modified Rankin score (mRS) is a scale for measuring the degree of disability or dependence of people who have suffered a stroke. 0 - no symptoms at all; 1 - no significant disability despite symptoms; able to carry out all usual duties and activities; 2- slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3- moderate disability; requiring some help, but able to walk without assistance; 4 - moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5 - severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6- dead. Patient centered utility weights are applied to these scores as 1.0 for mRS level 0; 0.91 for mRS level 1; 0.76 for mRS level 2; 0.65 for mRS level 3; 0.33 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 6. Unlike the mRS, the utility-weighted mRS runs from 0 to 1, with 0 being the worst. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Hemorrhagic Transformation | 36(+/-12) hrs after treatment initiation | Number of participants with any new bleeding within the infarcted brain tissue on 36(+/-12) hr MRI/CT scan after treatment initiation |
| Number of Participants With Symptomatic Hemorrhagic Transformation | 36(+/-12) hrs after treatment initiation | Defined as number of participants with any new bleeding within the infarcted brain tissue and an NIH Stroke Scale worsening of 4 or more points associated with the bleeding within 36 (+/-12) hrs of treatment initiation |
| Number of Participants With Neurological Worsening Associated With Antihypertensive Treatment | Treatment initiation to 24 hrs after treatment initiation | Defined as number of participants with 4 points of greater increase in NIH Stroke scale associated with reduction in SBP caused by anti-hypertensive treatment initiation or titration. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Compliance Outcome | Treatment initiation to 24 hrs after treatment Initiation | Number of participants with an hourly maximum SBP above target from 2-24 hrs post treatment initiation |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Higher Systolic Blood Pressure (SBP) Target Lower systolic blood pressure to ≤180 mmHg and maintain for 24 hours. If anti-hypertensive medication used, then maintain ≥160 mmHg.
Nicardipine: In the event where SBP values are above the randomly assigned target, intravenous nicardipine will be initiated at 2.5 mg/hr to lower the SBP. If SBP is still not reduced to below assigned target after 15 minutes, nicardipine dose will be increased by 2.5 mg/hr every 15 minutes until the target SBP or a maximum dose of 15 mg/hr is reached.
Labetalol: If SBP is above target despite maximum nicardipine infusion for 30 minutes, 10-20 mg of intravenous labetalol will be added every 15 minutes.
Hydralazine: If SBP remains unresponsive for 1 hr despite the use of maximum doses of nicardipine and labetalol, a Hydralazine will be added at the treating physician's discretion. Incidence of the latter scenario is anticipated to be exceedingly rare. | 40 |
| Lower SBP (<160 mmHg) Target Lower systolic blood pressure to \<160 mmHg and maintain for 24 hours. If anti-hypertensive medication used, then maintain \>140 mmHg.
Nicardipine: In the event where SBP values are above the randomly assigned target, intravenous nicardipine will be initiated at 2.5 mg/hr to lower the SBP. If SBP is still not reduced to below assigned target after 15 minutes, nicardipine dose will be increased by 2.5 mg/hr every 15 minutes until the target SBP or a maximum dose of 15 mg/hr is reached.
Labetalol: If SBP is above target despite maximum nicardipine infusion for 30 minutes, 10-20 mg of intravenous labetalol will be added every 15 minutes.
Hydralazine: If SBP remains unresponsive for 1 hr despite the use of maximum doses of nicardipine and labetalol, a Hydralazine will be added at the treating physician's discretion. Incidence of the latter scenario is anticipated to be exceedingly rare. | 40 |
| Lower SBP (<140mmHg) Target Lower systolic blood pressure to \<140 mmHg and maintain for 24 hours. If anti-hypertensive medication used, then maintain \>110 mmHg.
Nicardipine: In the event where SBP values are above the randomly assigned target, intravenous nicardipine will be initiated at 2.5 mg/hr to lower the SBP. If SBP is still not reduced to below assigned target after 15 minutes, nicardipine dose will be increased by 2.5 mg/hr every 15 minutes until the target SBP or a maximum dose of 15 mg/hr is reached.
Labetalol: If SBP is above target despite maximum nicardipine infusion for 30 minutes, 10-20 mg of intravenous labetalol will be added every 15 minutes.
Hydralazine: If SBP remains unresponsive for 1 hr despite the use of maximum doses of nicardipine and labetalol, a Hydralazine will be added at the treating physician's discretion. Incidence of the latter scenario is anticipated to be exceedingly rare. | 40 |
| Total | 120 |
Baseline characteristics
| Characteristic | Higher Systolic Blood Pressure (SBP) Target | Lower SBP (<160 mmHg) Target | Lower SBP (<140mmHg) Target | Total |
|---|---|---|---|---|
| Age, Continuous | 68 years | 70.5 years | 74 years | 71 years |
| Alberta Stroke Program Early CT score | 8 Scores on a Scale | 7 Scores on a Scale | 8 Scores on a Scale | 8 Scores on a Scale |
| Pre-stroke modified Rankin score | 0 units on a scale, 0-6 (6=death) | 0 units on a scale, 0-6 (6=death) | 0.5 units on a scale, 0-6 (6=death) | 0 units on a scale, 0-6 (6=death) |
| Race/Ethnicity, Customized Black Race | 5 Participants | 2 Participants | 2 Participants | 9 Participants |
| Race/Ethnicity, Customized Multi-racial | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White Race | 34 Participants | 37 Participants | 34 Participants | 105 Participants |
| Sex/Gender, Customized Female | 20 Participants | 21 Participants | 28 Participants | 69 Participants |
| Sex/Gender, Customized Male | 19 Participants | 19 Participants | 12 Participants | 50 Participants |
| Sex/Gender, Customized Unknown | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 40 | 6 / 40 | 3 / 40 |
| other Total, other adverse events | 0 / 40 | 0 / 40 | 0 / 40 |
| serious Total, serious adverse events | 1 / 40 | 3 / 40 | 4 / 40 |
Outcome results
Primary
Final Infarct Volume
Infarct volume on diffusion-weighted MRI (or CT if MRI cannot be obtained) at 36 (+/-12) hrs after treatment initiation, adjusted for the baseline CT perfusion core infract volume.
Time frame: 36 (+/-12) hrs after treatment initiation
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Higher Systolic Blood Pressure (SBP) Target | Final Infarct Volume | 46.4 Cubic Centimeters |
| Lower SBP (<160 mmHg) Target | Final Infarct Volume | 50.7 Cubic Centimeters |
| Lower SBP (<140mmHg) Target | Final Infarct Volume | 32.4 Cubic Centimeters |
Primary
Utility-weighted Modified Rankin Score
Modified Rankin score (mRS) is a scale for measuring the degree of disability or dependence of people who have suffered a stroke. 0 - no symptoms at all; 1 - no significant disability despite symptoms; able to carry out all usual duties and activities; 2- slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; 3- moderate disability; requiring some help, but able to walk without assistance; 4 - moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5 - severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6- dead. Patient centered utility weights are applied to these scores as 1.0 for mRS level 0; 0.91 for mRS level 1; 0.76 for mRS level 2; 0.65 for mRS level 3; 0.33 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 6. Unlike the mRS, the utility-weighted mRS runs from 0 to 1, with 0 being the worst.
Time frame: 90 days after treatment initiation
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Higher Systolic Blood Pressure (SBP) Target | Utility-weighted Modified Rankin Score | 0.58 units on a scale (Range 0-1; 1=best) |
| Lower SBP (<160 mmHg) Target | Utility-weighted Modified Rankin Score | 0.47 units on a scale (Range 0-1; 1=best) |
| Lower SBP (<140mmHg) Target | Utility-weighted Modified Rankin Score | 0.51 units on a scale (Range 0-1; 1=best) |
Secondary
Number of Participants With Any Hemorrhagic Transformation
Number of participants with any new bleeding within the infarcted brain tissue on 36(+/-12) hr MRI/CT scan after treatment initiation
Time frame: 36(+/-12) hrs after treatment initiation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Higher Systolic Blood Pressure (SBP) Target | Number of Participants With Any Hemorrhagic Transformation | 12 Participants |
| Lower SBP (<160 mmHg) Target | Number of Participants With Any Hemorrhagic Transformation | 12 Participants |
| Lower SBP (<140mmHg) Target | Number of Participants With Any Hemorrhagic Transformation | 14 Participants |
Secondary
Number of Participants With Neurological Worsening Associated With Antihypertensive Treatment
Defined as number of participants with 4 points of greater increase in NIH Stroke scale associated with reduction in SBP caused by anti-hypertensive treatment initiation or titration.
Time frame: Treatment initiation to 24 hrs after treatment initiation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Higher Systolic Blood Pressure (SBP) Target | Number of Participants With Neurological Worsening Associated With Antihypertensive Treatment | 0 Participants |
| Lower SBP (<160 mmHg) Target | Number of Participants With Neurological Worsening Associated With Antihypertensive Treatment | 0 Participants |
| Lower SBP (<140mmHg) Target | Number of Participants With Neurological Worsening Associated With Antihypertensive Treatment | 0 Participants |
Secondary
Number of Participants With Symptomatic Hemorrhagic Transformation
Defined as number of participants with any new bleeding within the infarcted brain tissue and an NIH Stroke Scale worsening of 4 or more points associated with the bleeding within 36 (+/-12) hrs of treatment initiation
Time frame: 36(+/-12) hrs after treatment initiation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Higher Systolic Blood Pressure (SBP) Target | Number of Participants With Symptomatic Hemorrhagic Transformation | 2 Participants |
| Lower SBP (<160 mmHg) Target | Number of Participants With Symptomatic Hemorrhagic Transformation | 1 Participants |
| Lower SBP (<140mmHg) Target | Number of Participants With Symptomatic Hemorrhagic Transformation | 2 Participants |
Other Pre-specified
Compliance Outcome
Number of participants with an hourly maximum SBP above target from 2-24 hrs post treatment initiation
Time frame: Treatment initiation to 24 hrs after treatment Initiation