Moderate Risk of CVD
Conditions
Keywords
Primary prevention of coronary heart disease, Stroke and cardiovascular death, Aspirin
Brief summary
The use of acetylsalicylic acid in the primary prevention of cardiovascular events has been extensively studied but to a lesser extent in patients with moderate levels of cardiovascular risk. The current study is designed to prove the efficacy and tolerability of 100 mg enteric-coated Aspirin versus placebo in the prevention of cardiovascular disease (CVD) events, which include fatal and nonfatal myocardial infarction, fatal and nonfatal stroke and CV death, in a population with no history of known CVD who are at moderate risk of major CHD events (approximately 10-20% 10 year CHD risk). This corresponds to a patient population mean 10-year CVD risk of approximately 30%. Subjects are treated in a standard care setting and may receive treatment for the underlying risk factors as defined by the treating physician. Outcome events will be adjudicated by an Endpoint Adjudication Committee and the study will be monitored by an independent Data Safety Monitoring Board.
Detailed description
Summary of substantial Protocol amendments Amendment #2 from 09-APR-2008: * Systolic blood pressure (SBP) limit of 170 mmHg has been added to the exclusion criteria * Exclusion of patients currently taking anticoagulant medication * A longer interval between the daily dose of study drug and ibuprofen * Revised wording in moderate risk definitions for coronary heart disease (CHD) and cerebrovascular disease (CVD): To evaluate the clinical effects of a 100 mg/day enteric-coated acetylsalicylic acid versus placebo in the reduction of CVD events in patients at moderate risk of major CHD events (approximately 10 to 20% 10-year CHD risk; approximately 20 to 30% 10-year risk of CVD). This corresponds to a patient population mean 10-year CVD risk of approximately 30%. Amendment #3 from 02-JAN-2009 • Increase in the number of allowed risk factors for males, age is no longer a risk factor Amendment #4 from 02-OCT-2013 * The primary endpoint is changed to include confirmed UA and TIA. * The estimated event rate is changed to 1.5% per year due to new information. * Effect size (risk reduction) changed from 14.9% to 17 to 18%. * Achieving 60,000 person-years instead of 1488 primary endpoint events * Additional treatment and follow-up for a maximum of another 12 months. * Change to reduced adverse event and concomitant therapy reporting
Interventions
100mg enteric coated Aspirin, taken daily
DRUGPlacebo
Placebo, taken daily
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males aged 55 years and above with 2 to 4 risk factors. Male Risk Factors: * Elevated cholesterol (Tchol\>200 mg/dL or LDL\>130 mg/dL; as measured at screening) irrespective of current treatment * Current smoking: defined as any cigarette smoking in the past 12 months * Low HDL cholesterol (HDL\<40 mg/dL; as measured at screening) * Elevated blood pressure (SBP\>140 mmHg; as measured at screening) * Currently on any medication to treat high blood pressure * Positive family history of early CHD (a first-degree relative \[father, mother, brother, sister, son, daughter\] suffered a heart attack \[myocardial infarction\] before the age of 60 years) * Females aged 60 and above with 3 or more risk factors. Female Risk Factors: * Elevated cholesterol (Tchol\>240 mg/dL or LDL\>160 mg/dL; as measured at screening) irrespective of current treatment * Current smoking: defined as any cigarette smoking in the past 12 months * Low HDL cholesterol (HDL\<40 mg/dL; as measured at screening) * Elevated blood pressure (SBP\>140 mmHg; as measured at screening) * Currently on any medication to treat high blood pressure * Positive family history of early CHD (a first-degree relative \[father, mother, brother, sister, son, daughter\] suffered a heart attack \[myocardial infarction\] before the age of 60 years) * An understanding and willingness to comply with trial procedures and has given written informed consent to participate in the trial
Exclusion criteria
* History of a documented vascular event, such as MI, stroke, coronary artery angioplasty or stenting, coronary artery bypass graft, relevant arrhythmias, or congestive heart failure or vascular intervention * Patients who are at higher than moderate risk on the basis of their diabetes status, other factors known to the investigator, or the currently used national risk score * Known contraindications to the study drug, e.g. hypersensitivity to acetylsalicylic acid * Recent (in the past year) history of gastrointestinal or genitourinary bleeding or other bleeding disorders * Active diagnosed and documented reflux esophagitis * Patients presenting with any medical condition, or psychiatric or substance abuse disorder, that, in the opinion of the investigator, is likely to affect the patient's ability to complete the study or precludes the patient's participation in the study * Lactating women or women of childbearing potential * Severe liver disease or damage based on the clinical judgment of the investigator * Severe renal disease or damage based on the clinical judgement of the investigator * A definite indication for acetylsalicylic acid therapy, other antiplatelet drug, or anticoagulant in the opinion of the physician * A history of asthma induced by administration of salicylates or substances with a similar action, notably NSAIDS * Chronic, frequent (\> 5 days/month) use of NSAIDs (including aspirin, or aspirin containing products), COX-2 inhibitors or metamizole * Current participation in any other trials involving investigational products within 30 days prior to the Screening Visit * Current use of an anticoagulant medication * Sitting systolic blood pressure greater than 170 mmHg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack) | Until follow-up (approximate 6 years) | The primary efficacy endpoint was a composite outcome consisting of the first occurrence of confirmed MI, stroke, cardiovascular death, UA, TIA. The time to event was defined as the number of days from the date of randomization to the date of the event confirmed by adjudication. The numbers of days for milestones when 1%, 2%, 3% and 4% of the subjects have reached endpoint events were estimated from Kaplan-Meier-Analyses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Until follow-up (approximately 6 years) | The time to event was defined as the number of days from the date of randomization to the date of the event confirmed by adjudication. The numbers of days for milestones when 1%, 2%, 3% and 4% of the subjects have reached endpoint events were estimated from Kaplan-Meier-Analyses. |
| Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Until follow-up (approximately 6 years) | The time to event was defined as the number of days from the date of randomization to the date of the event confirmed by adjudication. The numbers of days for milestones when 1%, 2%, 3% and 4% of the subjects have reached endpoint events were estimated from Kaplan-Meier-Analyses. |
| Incidence of All-cause Mortality, All Cancers Excluding Non-melanoma Skin Cancer and Colon Cancer | Until follow-up (approximately 6 years) | — |
| Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | Until follow-up (approximately 6 years) | The percentages of subjects with the efficacy endpoints of confirmed MI, stroke, cardiovascular death, UA and TIA are reported separately. \*all other CV death without fatal MI and fatal stroke |
| Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown) | Until follow-up (approximate 6 years) | The time to Composite outcome consisting of the first occurrence of cardiovascular death, MI, or stroke (ischemic, hemorrhagic, or unknown) was defined as the number of days from the date of randomization to the date of the event confirmed by adjudication. The numbers of days for milestones when 1%, 2%, 3% and 4% of the subjects have reached endpoint events were estimated from Kaplan-Meier-Analyses. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adjudicated GI Bleeding by Severity | Until follow-up (approximate 6 years) | — |
| Incidence of Composite Outcomes and Non-fatal MI | Until follow-up (approximate 6 years) | — |
| Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | Until follow-up (approximate 6 years) | \*all other CV death without fatal MI and fatal stroke. |
Countries
Germany, Ireland, Italy, Poland, Puerto Rico, Spain, United Kingdom, United States
Participant flow
Recruitment details
Overall, 15823 subjects were screened. Of these, 3277 subjects were screening failures. The remaining 12546 subjects were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) Subjects received 1 tablet of enteric-coated acetylsalicylic acid \[100 milligram (mg)\] orally once daily. | 6,270 |
| Placebo Subjects received 1 tablets of matching placebo orally once daily. | 6,276 |
| Total | 12,546 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 129 | 122 |
| Overall Study | Clinical endpoint reached | 110 | 123 |
| Overall Study | Consent withdrawn by subject | 817 | 873 |
| Overall Study | Death | 140 | 137 |
| Overall Study | Insufficient therapeutic effect | 4 | 5 |
| Overall Study | Lost to Follow-up | 210 | 198 |
| Overall Study | Missing end-of-study page | 91 | 92 |
| Overall Study | Non-compliant with study treatment | 23 | 16 |
| Overall Study | Not treated | 25 | 17 |
| Overall Study | Other | 236 | 239 |
| Overall Study | Protocol Violation | 80 | 69 |
| Overall Study | Reason not given | 3 | 1 |
Baseline characteristics
| Characteristic | Acetylsalicylic Acid (Aspirin, BAYE4465) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63.9 Years STANDARD_DEVIATION 7.1 | 63.9 Years STANDARD_DEVIATION 7.05 | 63.9 Years STANDARD_DEVIATION 7.08 |
| Sex: Female, Male Female | 1851 Participants | 1857 Participants | 3708 Participants |
| Sex: Female, Male Male | 4419 Participants | 4419 Participants | 8838 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5,053 / 6,276 | 5,059 / 6,270 |
| serious Total, serious adverse events | 1,311 / 6,276 | 1,266 / 6,270 |
Outcome results
Primary
Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack)
The primary efficacy endpoint was a composite outcome consisting of the first occurrence of confirmed MI, stroke, cardiovascular death, UA, TIA. The time to event was defined as the number of days from the date of randomization to the date of the event confirmed by adjudication. The numbers of days for milestones when 1%, 2%, 3% and 4% of the subjects have reached endpoint events were estimated from Kaplan-Meier-Analyses.
Time frame: Until follow-up (approximate 6 years)
Population: Intention-to-treat. The intent-to-treat (ITT) group (N=12546) consists of all patients who were randomized to the assigned study drug.
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack) | Days until 1% subjects had an efficacy event | 528 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack) | Days until 2% subjects had an efficacy event | 889 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack) | Days until 3% subjects had an efficacy event | 1225 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack) | Days until 4% subjects had an efficacy event | 1630 Days |
| Placebo | Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack) | Days until 4% subjects had an efficacy event | 1582 Days |
| Placebo | Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack) | Days until 1% subjects had an efficacy event | 381 Days |
| Placebo | Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack) | Days until 3% subjects had an efficacy event | 1134 Days |
| Placebo | Time to the First Occurrence of the Composite Outcome of MI (Myocardial Infarction), Stroke, Cardiovascular Death, UA (Unstable Angina) or TIA (Transient Ischemic Attack) | Days until 2% subjects had an efficacy event | 796 Days |
Comparison: Primary efficacy analysis of time to the composite endpoint was conducted via a 2-sided log-rank test stratified for treatment, country, and sex. Results would be considered statistically significant and the primary objective of the study will have been met if the 2-sided P value is ≤0.05.p-value: 0.597Log Rank
Secondary
Incidence of All-cause Mortality, All Cancers Excluding Non-melanoma Skin Cancer and Colon Cancer
Time frame: Until follow-up (approximately 6 years)
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of All-cause Mortality, All Cancers Excluding Non-melanoma Skin Cancer and Colon Cancer | all-cause mortality | 2.55 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of All-cause Mortality, All Cancers Excluding Non-melanoma Skin Cancer and Colon Cancer | all cancers excluding non-melanoma skin cancer | 4.02 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of All-cause Mortality, All Cancers Excluding Non-melanoma Skin Cancer and Colon Cancer | colon cancer | 0.48 Percentage of participants |
| Placebo | Incidence of All-cause Mortality, All Cancers Excluding Non-melanoma Skin Cancer and Colon Cancer | all-cause mortality | 2.57 Percentage of participants |
| Placebo | Incidence of All-cause Mortality, All Cancers Excluding Non-melanoma Skin Cancer and Colon Cancer | all cancers excluding non-melanoma skin cancer | 3.76 Percentage of participants |
| Placebo | Incidence of All-cause Mortality, All Cancers Excluding Non-melanoma Skin Cancer and Colon Cancer | colon cancer | 0.41 Percentage of participants |
Comparison: Analysis of incidence of all-cause mortality was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.945995% CI: [0.8, 1.24]Log Rank
Secondary
Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately
The percentages of subjects with the efficacy endpoints of confirmed MI, stroke, cardiovascular death, UA and TIA are reported separately. \*all other CV death without fatal MI and fatal stroke
Time frame: Until follow-up (approximately 6 years)
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | stroke | 1.20 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | UA | 0.32 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | CV death* | 0.61 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | TIA | 0.67 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | MI | 1.52 Percentage of participants |
| Placebo | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | TIA | 0.72 Percentage of participants |
| Placebo | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | MI | 1.78 Percentage of participants |
| Placebo | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | stroke | 1.07 Percentage of participants |
| Placebo | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | CV death* | 0.62 Percentage of participants |
| Placebo | Incidence of Confirmed MI, Stroke, Cardiovascular Death, UA, and TIA Separately | UA | 0.32 Percentage of participants |
Comparison: Analysis of incidence of MI was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.232595% CI: [0.64, 1.11]Log Rank
Comparison: Analysis of incidence of stroke was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.507295% CI: [0.8, 1.55]Log Rank
Comparison: Analysis of incidence of cardiovascular death was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.90195% CI: [0.62, 1.52]Log Rank
Comparison: Analysis of incidence of UA was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.997995% CI: [0.54, 1.86]Log Rank
Comparison: Analysis of incidence of TIA was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.745595% CI: [0.61, 1.42]Log Rank
Secondary
Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer
The time to event was defined as the number of days from the date of randomization to the date of the event confirmed by adjudication. The numbers of days for milestones when 1%, 2%, 3% and 4% of the subjects have reached endpoint events were estimated from Kaplan-Meier-Analyses.
Time frame: Until follow-up (approximately 6 years)
Population: ITT
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 1% subjects had all-cause mortality | 838 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 2% subjects had all-cause mortality | 1493 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 3% subjects had all-cause mortality | 1970 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 4% subjects had all-cause mortality | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 1% subjects had all cancer excl. NMSC | 374 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 2% subjects had all cancer excl. NMSC | 849 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 3% subjects had all cancer excl. NMSC | 1164 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 4% subjects had all cancer excl. NMSC | 1542 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 1% subjects had colon cancer | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 2% subjects had colon cancer | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 3% subjects had colon cancer | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 4% subjects had colon cancer | NA Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 3% subjects had colon cancer | NA Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 1% subjects had all-cause mortality | 938 Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 3% subjects had all cancer excl. NMSC | 1276 Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 2% subjects had all-cause mortality | 1460 Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 2% subjects had colon cancer | NA Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 3% subjects had all-cause mortality | 1963 Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 4% subjects had all cancer excl. NMSC | 1751 Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 4% subjects had all-cause mortality | NA Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 4% subjects had colon cancer | NA Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 1% subjects had all cancer excl. NMSC | 420 Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 1% subjects had colon cancer | NA Days |
| Placebo | Time to All-cause Mortality, the First Occurrence of All Cancers Excluding Non-melanoma Skin Cancer (NMSC) and the First Occurrence of Colon Cancer | Days until 2% subjects had all cancer excl. NMSC | 805 Days |
Comparison: Analysis of time to the first occurence colon cancer was conducted via a 2-sided log-rank test stratified for treatment, country, and sex. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.611Log Rank
Comparison: Analysis of time to all-cause mortality was conducted via a 2-sided log-rank test stratified for treatment, country, and sex. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.9544Log Rank
Comparison: Analysis of time to the first occurrence of all cancers excluding non-melanoma skin cancer was conducted via a 2-sided log-rank test stratified for treatment, country, and sex. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.4422Log Rank
Secondary
Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown)
The time to Composite outcome consisting of the first occurrence of cardiovascular death, MI, or stroke (ischemic, hemorrhagic, or unknown) was defined as the number of days from the date of randomization to the date of the event confirmed by adjudication. The numbers of days for milestones when 1%, 2%, 3% and 4% of the subjects have reached endpoint events were estimated from Kaplan-Meier-Analyses.
Time frame: Until follow-up (approximate 6 years)
Population: ITT
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown) | Days until 1% subjects had an efficacy event | 678 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown) | Days until 2% subjects had an efficacy event | 1167 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown) | Days until 3% subjects had an efficacy event | 1599 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown) | Days until 4% subjects had an efficacy event | 1949 Days |
| Placebo | Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown) | Days until 4% subjects had an efficacy event | 1930 Days |
| Placebo | Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown) | Days until 1% subjects had an efficacy event | 522 Days |
| Placebo | Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown) | Days until 3% subjects had an efficacy event | 1501 Days |
| Placebo | Time to the First Occurrence of the Composite Outcome of Cardiovascular Death, MI, or Stroke (Ischemic, Hemorrhagic, or Unknown) | Days until 2% subjects had an efficacy event | 1053 Days |
Comparison: Statistics for time to the composite endpoint was conducted via a 2-sided log-rank test stratified for treatment, country, and sex. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.6125Log Rank
Secondary
Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA
The time to event was defined as the number of days from the date of randomization to the date of the event confirmed by adjudication. The numbers of days for milestones when 1%, 2%, 3% and 4% of the subjects have reached endpoint events were estimated from Kaplan-Meier-Analyses.
Time frame: Until follow-up (approximately 6 years)
Population: ITT
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had non-fatal MI | 1309 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had non-fatal MI | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had total MI | 1216 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had total MI | 2128 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had non-fatal stroke | 1576 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had non-fatal stroke | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had total stroke | 1543 Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had total stroke | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had cardiovascular death | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had cardiovascular death | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had UA | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had UA | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had TIA | NA Days |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had TIA | NA Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had UA | NA Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had non-fatal MI | 1085 Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had total stroke | NA Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had non-fatal MI | 2121 Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had TIA | NA Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had total MI | 1014 Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had cardiovascular death | NA Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had total MI | 1906 Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had UA | NA Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had non-fatal stroke | 1650 Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had cardiovascular death | NA Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had non-fatal stroke | NA Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 2% subjects had TIA | NA Days |
| Placebo | Time to the First Occurrence of the Individual Components of the Primary: Non-fatal MI, Total MI, Non-fatal Stroke, Total Stroke, Cardiovascular Death, UA and TIA | Days until 1% subjects had total stroke | 1627 Days |
Comparison: Statistics for time to non-fatal MI was conducted via a 2-sided log-rank test stratified for treatment, country, and sex. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.4505Log Rank
Comparison: Statistics for time to total MI was conducted via a 2-sided log-rank test stratified for treatment, country, and sex. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.229Log Rank
Comparison: Statistics for time to total non-fatal stroke was conducted via a 2-sided log-rank test stratified for treatment, country, and sex. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.3947Log Rank
Comparison: Statistics for time to total stroke was conducted via a 2-sided log-rank test stratified for treatment, country, and sex. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.5125Log Rank
Other Pre-specified
Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population
\*all other CV death without fatal MI and fatal stroke.
Time frame: Until follow-up (approximate 6 years)
Population: Per-protocol (PP) group (N=7702) consists of all patients who had no protocol violation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | MI, stroke or CV death | 2.72 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | CV death* | 0.69 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | Non-fatal MI | 0.84 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | UA | 0.21 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | MI | 0.98 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | TIA | 0.50 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | Stroke | 1.06 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | All-cause mortality | 2.85 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | MI, stroke, CV death, UA or TIA | 3.40 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | All-cause mortality | 2.58 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | MI, stroke, CV death, UA or TIA | 4.19 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | MI, stroke or CV death | 3.45 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | MI | 1.84 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | Non-fatal MI | 1.53 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | Stroke | 0.95 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | CV death* | 0.66 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | UA | 0.28 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Individual Outcomes in Per-protocol Population | TIA | 0.49 Percentage of participants |
Comparison: Analysis of incidence of composite outcome of MI, stroke, CV death, UA or TIA was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.075695% CI: [0.64, 1.02]Log Rank
Comparison: Analysis of incidence of composite outcome of MI, stroke or CV death was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.066195% CI: [0.61, 1.02]Log Rank
Comparison: Analysis of incidence of MI was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.001495% CI: [0.36, 0.79]Log Rank
Comparison: Analysis of incidence of non-fatal MI was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.005695% CI: [0.36, 0.84]Log Rank
Comparison: Analysis of incidence of stroke was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.629195% CI: [0.71, 1.75]Log Rank
Comparison: Analysis of incidence of CV death was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.916195% CI: [0.6, 1.77]Log Rank
Comparison: Analysis of incidence of UA was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.53895% CI: [0.3, 1.87]Log Rank
Comparison: Analysis of incidence of TIA was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.918195% CI: [0.55, 1.95]Log Rank
Comparison: Analysis of incidence of all-cause mortality was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.479695% CI: [0.84, 1.45]Log Rank
Other Pre-specified
Incidence of Composite Outcomes and Non-fatal MI
Time frame: Until follow-up (approximate 6 years)
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Non-fatal MI | non-fatal MI | 1.40 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Non-fatal MI | MI, stroke, CV death, UA or TIA | 4.29 Percentage of participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Incidence of Composite Outcomes and Non-fatal MI | MI, stroke or CV death | 3.32 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Non-fatal MI | non-fatal MI | 1.56 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Non-fatal MI | MI, stroke, CV death, UA or TIA | 4.48 Percentage of participants |
| Placebo | Incidence of Composite Outcomes and Non-fatal MI | MI, stroke or CV death | 3.47 Percentage of participants |
Comparison: Analysis of incidence of composite outcome of MI, stroke, CV death, UA or TIA was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.603895% CI: [0.81, 1.13]Log Rank
Comparison: Analysis of incidence of composite outcome of MI, stroke or CV death was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.61995% CI: [0.79, 1.15]Log Rank
Comparison: Analysis of incidence of non-fatal MI was conducted via a 2-sided log-rank test. Results would be considered statistically significant if the 2-sided P value is ≤0.05.p-value: 0.456295% CI: [0.67, 1.2]Log Rank
Other Pre-specified
Number of Subjects With Adjudicated GI Bleeding by Severity
Time frame: Until follow-up (approximate 6 years)
Population: ITT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Number of Subjects With Adjudicated GI Bleeding by Severity | Total | 61 Participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Number of Subjects With Adjudicated GI Bleeding by Severity | Mild | 42 Participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Number of Subjects With Adjudicated GI Bleeding by Severity | Moderate | 15 Participants |
| Acetylsalicylic Acid (Aspirin, BAYE4465) | Number of Subjects With Adjudicated GI Bleeding by Severity | Severe | 4 Participants |
| Placebo | Number of Subjects With Adjudicated GI Bleeding by Severity | Severe | 2 Participants |
| Placebo | Number of Subjects With Adjudicated GI Bleeding by Severity | Total | 29 Participants |
| Placebo | Number of Subjects With Adjudicated GI Bleeding by Severity | Moderate | 5 Participants |
| Placebo | Number of Subjects With Adjudicated GI Bleeding by Severity | Mild | 22 Participants |