A Study to Assess the Efficacy and Safety of Enteric-Coated Acetylsalicylic Acid in Patients at Moderate Risk of Cardiovascular Disease

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

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