Cerebrovascular Accident
Conditions
Brief summary
Phase III study to compare the preventive effect of recurrent brain infarction and safety of Aggrenox (combination drug containing sustained-release dipyridamole 200 mg/acetylsalicylic acid 25 mg) twice daily vs. acetylsalicylic acid 81 mg once daily
Interventions
DRUGAggrenox capsule
extended-release dipyridamole 200 mg plus ASA 50 mg in a capsule, 2 capsules twice daily
Acetylsalicylic Acid (ASA) 81 mg, 1 tablet once daily
Sponsors
Boehringer Ingelheim
Study design
Intervention model
PARALLEL
Primary purpose
PREVENTION
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients with a diagnosis of cerebral infarction (excluding cardiogenic cerebral embolism) who meet the diagnostic criteria based on the National Institute of Neurological Disorders and Stroke (NINDS) ad hoc committee's classification of cerebrovascular disease III. 1. Patients who have had an onset of cerebral infarction, the time of which is known, between 1 week and 6 months before the time of enrolment (including first and recurrent cerebral infarctions) 2. Patients who are 50 years or older 3. Patients whose neurological signs and symptoms are considered to be stable by the investigator or sub-investigator 4. Patients with a finding corresponding to the responsible focus confirmed by head X-ray computerised tomography (CT) or magnetic resonance imaging (MRI) 5. Patients who have at least two of the following risk factors: * diabetes * hypertension (systolic blood pressure is 140 mmHg or higher or diastolic blood pressure is 90 mmHg or higher) or under treatment of hypertension * smoker (at the time of onset of cerebral infarction) * obesity (Body mass index (BMI) is more than 25 kg/m2) * previous vascular disease (stroke, acute myocardial infarction or peripheral arterial disease before the onset of cerebral infarction) * end-organ damage (retinopathy, left ventricular hypertrophy (LVH) or microalbuminuria) * hyperlipidaemia
Exclusion criteria
1. Patients with a diagnosis of brain disorders with a bleeding risk such as brain haemorrhage, subarachnoid haemorrhage, cerebral arteriovenous (AV) malformation, cerebral AV aneurysms and brain tumours 2. Patients with complications of cardiac disorders (atrial fibrillation, mitral valve stenosis, severe cardiac valve disorders) that may provide an embolic source for cerebral embolism 3. Patients having had acute coronary syndromes (acute myocardial infarction, unstable angina) within 6 months after enrolment in this study 4. Patient with hypersensitivity to dipyridamole preparations 5. Patients with a history of drug allergy to acetylsalicylic acid (ASA) or aspirin asthma 6. Patients with a history of peptic ulcer 7. Patients having undergone arterial reconstruction after development of cerebral infarction 8. Patients with very severe impairment (4 or 5 on Modified Rankin Scale) 9. Patients with bleeding or bleeding tendencies (haemophilia, haemorrhage urinary tract, vitreous haemorrhage, etc.) 10. Patients with severe hypertension (systolic blood pressure is 180 mmHg or higher or diastolic blood pressure is 110 mmHg or higher) 11. Patients with complications such as serious cardiac, renal and hepatic disorders 12. Patients with a malignant tumour or having had a tumour treatment in the past 5 years 13. Women who are or may be pregnant or lactating women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With First Recurrent Cerebral Infarction (Fatal or Non-fatal) | Up to 124 weeks | All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Subarachnoid Haemorrhage | Up to 124 weeks | All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner. |
| Number of Patients With Transient Ischemic Attack (TIA) | Up to 124 weeks | All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner. |
| Number of Patients With Brain (Cerebral) Haemorrhage | Up to 124 weeks | All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner. |
| Number of Patients With Other Vascular Events | Up to 124 weeks | This endpoints were defined as pulmonary embolism, retinal vascular disorder, deep vein thrombosis, peripheral artery obstruction and vascular intervention. All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner. |
| Number of Patients With Ischemic Vascular Event Composite Endpoint | Up to 124 weeks | This is a composite endpoint of cerebral infarction, transient ischemic attack (TIA), acute myocardial infarction (MI), unstable angina and sudden death attributable to thromboembolism. All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner. |
| Number of Patients With Acute Coronary Syndrome (ACS) | Up to 124 weeks | ACS contains acute myocardial infarction (MI), unstable angina and sudden cardiac death. All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner. |
Countries
Japan
Participant flow
Recruitment details
Patient recruitment initiated from June 2006 and completed in December 2007.
Participants by arm
| Arm | Count |
|---|---|
| Aggrenox Capsule Aggrenox (extended-release dipyridamole 200 mg plus ASA 50 mg in a capsule), 2 capsules twice daily | 655 |
| Acetylsalicylic Acid (ASA) 81 mg Tablet ASA 81 mg, 1 tablet once daily | 639 |
| Total | 1,294 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 118 | 105 |
| Overall Study | IRB's rejection etc. | 10 | 3 |
| Overall Study | Lack of Efficacy | 58 | 42 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Protocol Violation | 7 | 6 |
| Overall Study | Withdrawal by Subject | 17 | 18 |
Baseline characteristics
| Characteristic | Aggrenox Capsule | Acetylsalicylic Acid (ASA) 81 mg Tablet | Total |
|---|---|---|---|
| Age, Continuous | 66.2 years STANDARD_DEVIATION 8.1 | 66.0 years STANDARD_DEVIATION 8.6 | 66.1 years STANDARD_DEVIATION 8.4 |
| Sex: Female, Male Female | 183 Participants | 186 Participants | 369 Participants |
| Sex: Female, Male Male | 472 Participants | 453 Participants | 925 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 634 / 655 | 604 / 639 |
| serious Total, serious adverse events | 178 / 655 | 167 / 639 |
Outcome results
Primary
Number of Patients With First Recurrent Cerebral Infarction (Fatal or Non-fatal)
All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With First Recurrent Cerebral Infarction (Fatal or Non-fatal) | 45 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With First Recurrent Cerebral Infarction (Fatal or Non-fatal) | 32 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.09795% CI: [0.93, 2.31]Regression, Cox
Secondary
Number of Patients With Acute Coronary Syndrome (ACS)
ACS contains acute myocardial infarction (MI), unstable angina and sudden cardiac death. All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With Acute Coronary Syndrome (ACS) | 9 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With Acute Coronary Syndrome (ACS) | 16 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.19295% CI: [0.26, 1.31]Regression, Cox
Secondary
Number of Patients With Brain (Cerebral) Haemorrhage
All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With Brain (Cerebral) Haemorrhage | 12 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With Brain (Cerebral) Haemorrhage | 7 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.22395% CI: [0.7, 4.54]Regression, Cox
Secondary
Number of Patients With Ischemic Vascular Event Composite Endpoint
This is a composite endpoint of cerebral infarction, transient ischemic attack (TIA), acute myocardial infarction (MI), unstable angina and sudden death attributable to thromboembolism. All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With Ischemic Vascular Event Composite Endpoint | 57 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With Ischemic Vascular Event Composite Endpoint | 51 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.44395% CI: [0.79, 1.69]Regression, Cox
Secondary
Number of Patients With Other Vascular Events
This endpoints were defined as pulmonary embolism, retinal vascular disorder, deep vein thrombosis, peripheral artery obstruction and vascular intervention. All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With Other Vascular Events | 11 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With Other Vascular Events | 6 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.21595% CI: [0.69, 5.07]Regression, Cox
Secondary
Number of Patients With Subarachnoid Haemorrhage
All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With Subarachnoid Haemorrhage | 0 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With Subarachnoid Haemorrhage | 1 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.998Regression, Cox
Secondary
Number of Patients With Transient Ischemic Attack (TIA)
All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With Transient Ischemic Attack (TIA) | 3 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With Transient Ischemic Attack (TIA) | 3 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.97795% CI: [0.21, 5.07]Regression, Cox
Post Hoc
Number of Patients With Composite Endpoint of Stroke or Major Bleeding
This is a composite endpoint of cerebral infarction, brain (cerebral) hemorrhage, subarachnoid haemorrhage and major bleeding. All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With Composite Endpoint of Stroke or Major Bleeding | 71 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With Composite Endpoint of Stroke or Major Bleeding | 55 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.10195% CI: [0.94, 1.91]Regression, Cox
Post Hoc
Number of Patients With Intracranial Haemorrhage
All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With Intracranial Haemorrhage | 13 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With Intracranial Haemorrhage | 13 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.91995% CI: [0.48, 2.25]Regression, Cox
Post Hoc
Number of Patients With Stroke
This is a composite endpoint of cerebral infarction, brain (cerebral) hemorrhage and subarachnoid haemorrhage. All events reported by investigators were adjudicated by the independent event assessment committee in a blinded manner.
Time frame: Up to 124 weeks
Population: All outcomes and efficacy endpoints were analysed on the basis of the full analysis set (FAS). FAS population excluded that 1) patients who did not meet inclusion criteria, 2) patients who had never taken the investigational products, and 3) patients who had no data after drug administration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aggrenox Capsule | Number of Patients With Stroke | 57 patients |
| Acetylsalicylic Acid (ASA) 81 mg Tablet | Number of Patients With Stroke | 39 patients |
Comparison: Non-event rate was calculated by using the Kaplan-Meier method and the comparison of groups was made by using the Cox proportional hazard regression model.p-value: 0.04395% CI: [1.01, 2.29]Regression, Cox