Cerebrovascular Accident
Conditions
Brief summary
German stroke units are hesitating to use Aggrenox for secondary ischaemic stroke / transient ischaemic attack (TIA) prevention in a sub-acute treatment setting. They argue that clinical experience with sub-acute Aggrenox treatment is limited and poorly documented when compared with sub-acute acetylsalicylic acid (ASA) treatment. However, long term treatment (started after 3-6 months after stroke/TIA) with Aggrenox was safe and superior to ASA treatment in preventing recurrent strokes. There is no evidence for ASA to prevent from neurological progression after stroke during the first 3 months. Results from a cohort study suggest that starting Aggrenox within 72 hours after stroke predicts clinical improvement in the National Institute of Health Stroke Scale (NIHSS) at discharge from the hospital. Dipyridamole suppresses acute inflammatory responses to stroke. This study is designed to investigate the tolerability and efficacy of a secondary stroke prevention treatment with Aggrenox when initiated within 24 hours of stroke onset on a stroke unit compared to later initiation after a 7 day ASA treatment and outside off a stroke unit setting.
Interventions
DRUGAggrenox bid (ASA 25mg/Dipyridamole ER 200mg)
DRUGASA 100 mg qd
Sponsors
Boehringer Ingelheim
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
-Clinical diagnosis of ischaemic stroke causing a measurable neurological deficit defined as impairment of language, motor function, cognition and/or gaze, vision or neglect. Symptoms must be distinguishable from an episode of generalised ischaemia (i.e. syncope), seizure, or migraine disorder. Main inclusion criteria: * Patients at risk of stroke who have had transient ischaemia of the brain or completed ischaemic stroke due to thrombosis * Symptoms of ischaemic attack began less than 24 hours prior to study medication start, are to be present for at least 30 minutes and have not significantly improved before start of treatment * Patients are eligible for platelet inhibiting treatment * National Institute of Health Stroke Scale (NIHSS) between 5 and 20 (at pre-screening and screening) * Actual Modified Rankin Scale (mRS) (at baseline) is worse than retrospective mRS (before stroke) * A contraindication for stroke lysis is given * Patients are able to give (at least oral) informed consent and to swallow either medication
Exclusion criteria
* Hypersensitivity to any of the components of the product or salicylates. * Patients with active gastric or duodenal ulcers or with bleeding disorders. * Pregnancy during the third trimester. * Lysis therapy. * A platelet inhibiting therapy with Acetylsalicylic Acid (ASA) doses of more than 100 mg per day, or with clopidogrel of any dose has been planned or started. * Time of onset of stroke symptoms is unknown (when a stroke happened during night-/sleeping time, bedtime is assumed as time of onset)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 90 days | The modified Rankin Scale (mRS) is a scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0-6, running from perfect health without symptoms to death. Best value - 0 (No symptoms), worst value - 6 (Dead) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patients With Relevant Event (Death, Non-fatal Stroke, Transient Ischaemic Attack (TIA), Myocardial Infarction (MI), Bleeding) | 90 days | — |
| Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 8 days | The modified Rankin Scale (mRS) is a scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0-6, running from perfect health without symptoms to death. Best value - 0 (No symptoms), worst value - 6 (Dead) |
| Change From Baseline in NIHSS (National Institutes of Health Stroke Scale) at Day 8 | Baseline and 8 days | The NIHSS is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. Values range from 0 (no deficit) to 42 (dead) |
| Change of Special Biochemical Laboratory Value- CRP | 8 days | Changes of special biochemical laboratory values (CRP) from baseline to day 8 - centralised, blinded assessment by a specialised central clinical laboratory |
| Change of Special Biochemical Laboratory Value- MMP-9 | 8 days | Changes of special biochemical laboratory value (MMP-9) from baseline to day 8 - centralised, blinded assessment by a specialised central clinical laboratory |
| Change From Baseline in NIHSS (National Institutes of Health Stroke Scale) | Baseline and 90 days | The NIHSS is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. Values range from 0 (no deficit) to 42 (dead) |
| Change From Baseline in FLAIR (Fluid-Attenuated Inversion Recovery) at Day 8 | Baseline and day 8 | MRI was performed to assess growth in stroke lesion volume by fluid-attenuated inversion recovery (FLAIR). |
| Change From Baseline in FLAIR (Fluid-Attenuated Inversion Recovery) at Day 90. | Baseline and day 90 | MRI was performed to assess growth in stroke lesion volume by fluid-attenuated inversion recovery (FLAIR). |
| Change From Baseline in DWI (Diffuse-Weighted Imaging) at Day 8 | Baseline and day 8 | MRI was performed to assess growth in stroke lesion volume by diffusion-weighted imaging (DWI). DWI was to give evidence of the development of the ischaemic lesion corresponding to the evolved stroke. |
| Change From Baseline in DWI (Diffuse-Weighted Imaging) at Day 90 | Baseline and day 90 | MRI was performed to assess growth in stroke lesion volume by diffusion-weighted imaging (DWI). DWI was to give evidence of the development of the ischaemic lesion corresponding to the evolved stroke. |
| Change of Special Biochemical Laboratory Value - MCP-1 | 8 days | Changes of special biochemical laboratory value (MCP-1) from baseline to day 8 - centralised, blinded assessment by a specialised central clinical laboratory |
Countries
Germany
Participant flow
Recruitment details
551 patients enrolled, 548 randomized, 543 treated; analysis is based on treated patients
Participants by arm
| Arm | Count |
|---|---|
| Aspirin for 7 Days, Followed by Aggrenox ASA 100 mg qd for 7 days, followed by Aggrenox (dipyridamole 200mg + ASA 25mg) b.i.d | 260 |
| Aggrenox Aggrenox (dipyridamole 200mg + ASA 25mg) b.i.d | 283 |
| Total | 543 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 40 | 58 |
| Overall Study | Lost to Follow-up | 12 | 4 |
| Overall Study | Other | 0 | 2 |
| Overall Study | Protocol Violation | 30 | 26 |
| Overall Study | Withdrawal by Subject | 10 | 9 |
Baseline characteristics
| Characteristic | Aspirin for 7 Days, Followed by Aggrenox | Aggrenox | Total |
|---|---|---|---|
| Age, Continuous | 68.3 Years STANDARD_DEVIATION 11.5 | 66.5 Years STANDARD_DEVIATION 11.4 | 67.3 Years STANDARD_DEVIATION 11.5 |
| Sex: Female, Male Female | 95 Participants | 109 Participants | 204 Participants |
| Sex: Female, Male Male | 165 Participants | 174 Participants | 339 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 60 / 260 | 119 / 283 |
| serious Total, serious adverse events | 48 / 260 | 45 / 283 |
Outcome results
Primary
Telephone Modified Rankin Scale (Centralised, Blinded Assessment)
The modified Rankin Scale (mRS) is a scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0-6, running from perfect health without symptoms to death. Best value - 0 (No symptoms), worst value - 6 (Dead)
Time frame: 90 days
Population: FAS which included all randomised patients who had follow up data available (mRS or NIHSS) or who were dead.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 2 | 50 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 4 | 31 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 1 | 75 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 5 | 6 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 3 | 30 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 6 | 4 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 0 | 58 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 6 | 5 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 0 | 70 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 1 | 84 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 2 | 62 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 3 | 16 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 4 | 32 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) | 5 | 4 participants |
Comparison: The primary endpoint tele-mRS on day 90 was available in 527 of 543 treated patients (97.1%).p-value: 0.68395% CI: [0.78, 1.461]Regression, Logistic
Secondary
Change From Baseline in DWI (Diffuse-Weighted Imaging) at Day 8
MRI was performed to assess growth in stroke lesion volume by diffusion-weighted imaging (DWI). DWI was to give evidence of the development of the ischaemic lesion corresponding to the evolved stroke.
Time frame: Baseline and day 8
Population: Full Analysis Set - included all randomised patients who had value in DWI at baseline and day 8.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Change From Baseline in DWI (Diffuse-Weighted Imaging) at Day 8 | -0.0600 mL |
| Aggrenox | Change From Baseline in DWI (Diffuse-Weighted Imaging) at Day 8 | 0.0000 mL |
Secondary
Change From Baseline in DWI (Diffuse-Weighted Imaging) at Day 90
MRI was performed to assess growth in stroke lesion volume by diffusion-weighted imaging (DWI). DWI was to give evidence of the development of the ischaemic lesion corresponding to the evolved stroke.
Time frame: Baseline and day 90
Population: Full Analysis Set - included all randomised patients who had value in DWI at baseline and day 90.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Change From Baseline in DWI (Diffuse-Weighted Imaging) at Day 90 | -0.8400 mL |
| Aggrenox | Change From Baseline in DWI (Diffuse-Weighted Imaging) at Day 90 | -0.7100 mL |
Secondary
Change From Baseline in FLAIR (Fluid-Attenuated Inversion Recovery) at Day 8
MRI was performed to assess growth in stroke lesion volume by fluid-attenuated inversion recovery (FLAIR).
Time frame: Baseline and day 8
Population: Full Analysis Set - included all randomised patients who had value in FLAIR at baseline and day 8.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Change From Baseline in FLAIR (Fluid-Attenuated Inversion Recovery) at Day 8 | 0.4100 mL |
| Aggrenox | Change From Baseline in FLAIR (Fluid-Attenuated Inversion Recovery) at Day 8 | 0.3300 mL |
Secondary
Change From Baseline in FLAIR (Fluid-Attenuated Inversion Recovery) at Day 90.
MRI was performed to assess growth in stroke lesion volume by fluid-attenuated inversion recovery (FLAIR).
Time frame: Baseline and day 90
Population: Full Analysis Set - included all randomised patients who had value in FLAIR at baseline and day 90.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Change From Baseline in FLAIR (Fluid-Attenuated Inversion Recovery) at Day 90. | 0.1900 mL |
| Aggrenox | Change From Baseline in FLAIR (Fluid-Attenuated Inversion Recovery) at Day 90. | 0.1150 mL |
Secondary
Change From Baseline in NIHSS (National Institutes of Health Stroke Scale)
The NIHSS is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. Values range from 0 (no deficit) to 42 (dead)
Time frame: Baseline and 90 days
Population: FAS which included all randomised patients who had follow up data available (mRS or NIHSS) or who were dead.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Change From Baseline in NIHSS (National Institutes of Health Stroke Scale) | -2 Units on a scale |
| Aggrenox | Change From Baseline in NIHSS (National Institutes of Health Stroke Scale) | -2 Units on a scale |
Comparison: Early treatment initiation (immediately after the index event) with Aggrenox was compared to late initiation of Aggrenox after 7 days of treatment with ASA monop-value: 0.607ANCOVA
Secondary
Change From Baseline in NIHSS (National Institutes of Health Stroke Scale) at Day 8
The NIHSS is a systematic assessment tool that provides a quantitative measure of stroke-related neurologic deficit. Values range from 0 (no deficit) to 42 (dead)
Time frame: Baseline and 8 days
Population: FAS which included all randomised patients who had follow up data available (mRS or NIHSS) or who were dead.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Change From Baseline in NIHSS (National Institutes of Health Stroke Scale) at Day 8 | -1.0 units on a scale |
| Aggrenox | Change From Baseline in NIHSS (National Institutes of Health Stroke Scale) at Day 8 | -1.0 units on a scale |
Secondary
Change of Special Biochemical Laboratory Value- CRP
Changes of special biochemical laboratory values (CRP) from baseline to day 8 - centralised, blinded assessment by a specialised central clinical laboratory
Time frame: 8 days
Population: FAS which included all randomised patients who had follow up data available (mRS or NIHSS) or who were dead.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Change of Special Biochemical Laboratory Value- CRP | 1.27 mg/L |
| Aggrenox | Change of Special Biochemical Laboratory Value- CRP | 1.17 mg/L |
Secondary
Change of Special Biochemical Laboratory Value - MCP-1
Changes of special biochemical laboratory value (MCP-1) from baseline to day 8 - centralised, blinded assessment by a specialised central clinical laboratory
Time frame: 8 days
Population: FAS which included all randomised patients who had follow up data available (mRS or NIHSS) or who were dead.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Change of Special Biochemical Laboratory Value - MCP-1 | 1.06 µg/mL |
| Aggrenox | Change of Special Biochemical Laboratory Value - MCP-1 | 1.08 µg/mL |
Secondary
Change of Special Biochemical Laboratory Value- MMP-9
Changes of special biochemical laboratory value (MMP-9) from baseline to day 8 - centralised, blinded assessment by a specialised central clinical laboratory
Time frame: 8 days
Population: FAS which included all randomised patients who had follow up data available (mRS or NIHSS) or who were dead.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Change of Special Biochemical Laboratory Value- MMP-9 | 0.974 ng/mL |
| Aggrenox | Change of Special Biochemical Laboratory Value- MMP-9 | 0.983 ng/mL |
Secondary
Patients With Relevant Event (Death, Non-fatal Stroke, Transient Ischaemic Attack (TIA), Myocardial Infarction (MI), Bleeding)
Time frame: 90 days
Population: FAS which included all randomised patients who had follow up data available (mRS or NIHSS) or who were dead.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Patients With Relevant Event (Death, Non-fatal Stroke, Transient Ischaemic Attack (TIA), Myocardial Infarction (MI), Bleeding) | 38 participants |
| Aggrenox | Patients With Relevant Event (Death, Non-fatal Stroke, Transient Ischaemic Attack (TIA), Myocardial Infarction (MI), Bleeding) | 28 participants |
Comparison: Early treatment initiation (immediately after the index event) with Aggrenox was compared to late initiation of Aggrenox after 7 days of treatment with ASA monop-value: 0.20295% CI: [0.442, 1.189]Cox proportional hazards model
Secondary
Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8
The modified Rankin Scale (mRS) is a scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0-6, running from perfect health without symptoms to death. Best value - 0 (No symptoms), worst value - 6 (Dead)
Time frame: 8 days
Population: FAS which included all randomised patients who had follow up data available (mRS or NIHSS) or who were dead.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 0 | 46 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 1 | 59 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 2 | 42 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 3 | 39 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 4 | 51 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 5 | 12 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 6 | 0 participants |
| Aspirin for 7 Days, Followed by Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | Missing | 5 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | Missing | 8 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 0 | 47 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 4 | 44 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 1 | 74 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 6 | 2 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 2 | 52 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 5 | 8 participants |
| Aggrenox | Telephone Modified Rankin Scale (Centralised, Blinded Assessment) at Day 8 | 3 | 38 participants |