Aspirin Twice a Day in Patients With Diabetes and Acute Coronary Syndrome (ANDAMAN)

Aspirin With a Novel Twice-a-day Administration in Diabetic Patients With Acute Coronary Syndrome to Minimize Recurrence of Acute Ischemic Events or New Urgent Revascularization

To compare treatment with Aspirin Protect® twice a day (100 mg in the morning and 100 mg in the evening) versus Aspirin Protect® 100 mg once per day on a composite end-point of ischemic events in diabetic patients, or in patients with a known risk factor for non-optimal aspirin response (obesity, abdominal obesity or coronary event occurring with long-term aspirin),with acute coronary syndrome. It is expected that aspirin taken twice a day will reduce the occurrence of new ischemic event after acute coronary syndrome in diabetic patients or in patients with a known risk factor.

Study Overview

• Status: Active, not recruiting
• Conditions: Coronary Artery Disease; Obesity; Diabetes Mellitus; Acute Coronary Syndrome
• Intervention / Treatment: Drug: Novel strategy Aspirin; Drug: Conventional strategy Aspirin

Detailed Description

Patients who show high persistent platelet reactivity under aspirin are increasingly becoming an issue of clinical concern. Several studies have suggested that giving aspirin more frequently is very effective for reducing aspirin high persistent platelet reactivity, especially in diabetic patientsor in patients with a known risk factor. The aim of the study is to evaluate low dose of aspirin twice a day (compared to once a day) for the reduction of ischemic events in diabetic patients or in patients with a known risk factor, with acute coronary syndrome.

Experimental Design:

A multicenter, randomised, parallel group comparing aspirin given twice a day compared to once per day in diabetic patients, or in patients with a known risk factor for non-optimal aspirin response (obesity, abdominal obesity or coronary event occurring with long-term aspirin),with acute coronary syndrome.

Primary objective:

To compare treatment with Aspirin Protect® twice a day (100 mg in the morning and 100 mg in the evening) versus Aspirin Protect® 100 mg once per day on a composite end-point of ischemic events in diabetic patients, or in patients with a known risk factor for non-optimal aspirin response (obesity, abdominal obesity or coronary event occurring with long-term aspirin),with acute coronary syndrome.

Secondary objectives:

• To compare treatment with Aspirin Protect® twice a day (100 mg in the morning and 100 mg in the evening) versus Aspirin Protect® 100 mg once per day on net clinical benefit combining the ischemic and bleeding events in diabetic patients, or in patients with a known risk factor for non-optimal aspirin response (obesity, abdominal obesity or coronary event occurring with long-term aspirin),with acute coronary syndrome.
• To compare treatment with Aspirin Protect® twice a day (100 mg in the morning and 100 mg in the evening) versus Aspirin Protect® 100 mg once per day on cardiac events in diabetic patients, or in patients with a known risk factor for non-optimal aspirin response (obesity, abdominal obesity or coronary event occurring with long-term aspirin),with acute coronary syndrome.
• To compare treatment with Aspirin Protect® twice a day (100 mg in the morning and 100 mg in the evening) versus Aspirin Protect® 100 mg once per day in each of individual component of the main criterion.
• To confirm the safety of the innovative strategy (aspirin twice a day) concerning major bleeding events.

Study enrollment:

Multicentric national study involving 42 centers in France The duration is expected to be 24 months of recruitment. Patients will be randomized during the index hospitalization for acute coronary syndrome and before discharge between a conventional strategy of enteric coated aspirin 100mg per day with the standard of care or a innovative strategy of enteric coated aspirin 100mg morning and evening. Patients will be followed at one month, six months, one year and 18 months

Statistical analysis:

The study will include 2574 patients. We hypothesized that at 18 months, there will be an event rate of 22% for "death, MI, stroke, urgent revascularization, or acute arterial thrombotic event in the group treated with aspirin and we expect a decrease of the primary event of 20% (relative variation) using aspirin twice a day corresponding to an event rate of 17.6%.

A sample size of 1287 patients /group will allow an 80% power to detect this difference using a log-rank test at a two-sided 5% significance level. The study will include 2574 diabetic patients, or patients with a known risk factor for non-optimal aspirin response.

The primary analysis is based on the Intention To Treat population and the primary endpoint. The primary analysis on the primary endpoint will be carried out using a log-rank test for survival analysis. The 95% confidence interval of the hazard ratio will be presented. In addition the survival status during 18 months follow-up will be described by showing Kaplan-Meier curves.

Primary outcome according to pre-specified subgroups:

• Age: patients < 75 years or patient ≥75 years
• Gender: male or female
• Insulin vs no insulin treatment
• Type of acute coronary syndrome : STEMI vs NSTEMI
• Type of ADP inhibitor cotreatment
• Treatment strategy medical vs invasive (angioplasty or CABG surgery)
• Peripheral artery disease Yes/No
• GRACE score > or ≤140
• Left ventricular ejection fraction > or ≤ 40%
• Prior stroke Yes/No
• previous treatment with aspirin Yes/No
• initial HbA1C level > or ≤8%
• duration of diabetes > or ≤10 years
• Weight <60; 60-90; >90kg
• PPI use Yes/No

• Study Type: Interventional
• Enrollment (Actual): 2488
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Patrick HENRY, MD, PhD; Phone Number: (33) 1 49 95 82 24; Email: patrick.henry@lrb.aphp.fr
• Study Contact Backup: Name: Jean Guillaume DILLINGER, MD; Phone Number: (33) 1 49 95 85 74; Email: jean-guillaume.dillinger@lrb.aphp.fr

Study Locations

• France
  • Paris, France, 75010
    • Department of Cardiology - Lariboisiere Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

_ Diabetes mellitus defined as (≥ 1 item)

• Treated diabetes mellitus
• 2 fasting glucose levels ≥ 7 mmol/l after admission
• glucose level ≥ 11 mmol/l after admission (any moment)
• HbA1C ≥ 6.5%

OR

• Factor of aspirin lack of efficacy defined as (≥ 1 item)

  • Obesity defined as BMI≥27kg/m2
  • Waist circumference ≥ 88cm for women or ≥102cm for men
  • Index event occurring under chronic low dose of aspirin (<300mg)

• Acute coronary syndrome defined as

  • Acute coronary syndrome with ST-segment elevation (STEMI) is defined as chest pain (≥ 30min) with persistent ST-segment elevation in at least two contiguous leads (≥1mm) or a new left bundle-branch block and the intention to perform primary PCI or thrombolysis.
  • Acute coronary syndrome without ST-segment elevation (NSTEMI) is defined as universal myocardial definition: Detection of cardiac biomarker values elevation [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following:
• Symptoms of ischemia
• New or presumed new significant ST-segment-T wave (ST-T) changes except ST elevation
• Development of pathological Q waves in the ECG
• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
• Identification of an intracoronary thrombus by angiography
• included after the angiography showing stenosis ≥50% and before discharge
• signed informed consent and ≥18 years old

Exclusion Criteria:

• Allergy or contraindication to aspirin (Hypersensitivity to aspirin or any of the excipients, history of asthma induced by the administration of salicylates, ongoing peptic ulcer, constitutional or acquired haemorrhagic disease including gastrointestinal bleeding, history of hemorrhagic stroke and thrombocytopenia, pregnancy after 24 weeks of gestation, risk of bleeding, severe renal failure, severe hepatic impairment, uncontrolled severe heart failure
• Concomitant anticoagulation therapy that cannot be stopped
• Fibrinolytic therapy less than 24 hours.
• Unstable patients according to investigator: use of amine or mechanical device (IABP, ECMO or similar) or mechanical ventilation during index hospitalization
• Index event is an acute complication of coronary revascularization (PCI or CABG)
• Known serious hematological disorder
• Proven gastric or duodenal ulcer in the past 3 months
• Previous hemorrhagic stroke, previous cranial bleeding, intracranial neoplasia, arterio-venous malformation
• Any condition that may put the patient at risk or influence study result in the investigators' opinion (active cancer ….) or that increase the risk for non-compliance or being lost to follow-up
• Concomitant treatment with methotrexate or with chronic non-steroidal anti-inflammatory drug
• Pregnancy or lactation or woman of childbearing age without contraception
• Participant in an another investigational drug study within 30 days
• Patients under curatorship
• No social security

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 : Novel strategy; enteric coated aspirin 100 mg in the morning and 100 mg in the evening	Drug: Novel strategy Aspirin; Aspirin twice a day : enteric coated enteric coated aspirin given twice a day, 100 mg in the morning and 100 mg in the evening (i.e. 200mg/day)
Active Comparator: Arm 2 : Conventional strategy; enteric coated aspirin 100 mg in the morning	Drug: Conventional strategy Aspirin; Aspirin once day: enteric coated aspirin 100 mg in the morning (i.e. 100mg/day)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
first main vascular event occurring within the 18 months after randomization among the following: Death (any), Myocardial infarction, Stroke, Urgent coronary revascularization and/or stent thrombosis, Acute arterial thrombotic event	at18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Major bleeding (type 3 to 5 following BARC classification	at18 months
Net clinical benefit: Death (any), Myocardial infarction, Stroke, Urgent coronary revascularization and/or stent thrombosis, Acute arterial thrombotic event, Major bleeding	at18 months
Cardiac endpoint: Cardiovascular death / Myocardial infarction	at18 months
Death, myocardial infarction, stroke, urgent revascularization, stent thrombosis, acute arterial thrombotic event and major bleeding analyzed specifically and separately	at18 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Bayer
• Investigators: Principal Investigator: Patrick HENRY, MD, PhD, Assistance Publique

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2016
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: June 12, 2015
• First Submitted That Met QC Criteria: August 7, 2015
• First Posted (Estimated): August 13, 2015

Study Record Updates

• Last Update Posted (Actual): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 14, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Aspirin; Obesity; Coronary artery disease; Acute coronary syndrome; Diabetes mellitus; Secondary prevention
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Disease; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus; Syndrome; Acute Coronary Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: P141005; 2015-000947-18 (EudraCT Number)