Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE I) (ACTIVE I)

A Parallel Randomized Controlled Evaluation of Clopidogrel Plus Aspirin, With Factorial Evaluation of Irbesartan, for the Prevention of Vascular Events, in Patients With Atrial Fibrillation

The purpose of this study was to determine if Irbesartan compared to Placebo would reduce the risk of vascular events such as heart attack, stroke, non-cerebral thromboembolic event and death in patients with Atrial Fibrillation (AF) and with at least one major risk of vascular events.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Atrial Fibrillation
• Intervention / Treatment: Drug: Irbesartan; Drug: placebo

Detailed Description

ACTIVE I was one of the 3 separate but related trials of the ACTIVE program conducted in AF patients at risk of vascular events.

Patients were enrolled first into one of the 2 parallel trials of the ACTIVE program evaluating Clopidogrel:

• ACTIVE A comparing clopidogrel + acetylsalicylic acid (ASA) and ASA alone
• ACTIVE W comparing clopidogrel + ASA and oral anticoagulant (OAC).

Then those satisfying additional criteria related to blood pressure and angiotensin receptor blocking agents were re-randomized in the two ACTIVE I arms according to a separate randomization list.

• Study Type: Interventional
• Enrollment (Actual): 9016
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanofi-Aventis Administrative Office
• Australia
  • Macquarie Park, Australia
    • Sanofi-Aventis Administrative Office
• Austria
  • Wien, Austria
    • Sanofi-Aventis Administrative Office
• Belgium
  • Diegem, Belgium
    • Sanofi-Aventis Administrative Office
• Brazil
  • Sao Paulo, Brazil
    • Sanofi-Aventis Administrative Office
• Canada
  • Laval, Canada
    • Sanofi-Aventis Administrative Office
• Chile
  • Santiago, Chile
    • Sanofi-Aventis Administrative Office
• Czech Republic
  • Praha, Czech Republic
    • Sanofi-Aventis Administrative Office
• Denmark
  • Horsholm, Denmark
    • Sanofi-Aventis Administrative Office
• Finland
  • Helsinki, Finland
    • Sanofi-Aventis Administrative Office
• France
  • Paris, France
    • Sanofi-Aventis Administrative Office
• Germany
  • Berlin, Germany
    • Sanofi-Aventis Administrative Office
• Greece
  • Athens, Greece
    • Sanofi-Aventis Administrative Office
• Hong Kong
  • Causeway Bay, Hong Kong
    • Sanofi-Aventis Administrative Office
• Hungary
  • Budapest, Hungary
    • Sanofi-Aventis Administrative Office
• Italy
  • Milano, Italy
    • Sanofi-Aventis Administrative Office
• Malaysia
  • Kuala Lumpur, Malaysia
    • Sanofi-Aventis Administrative Office
• Mexico
  • Mexico, Mexico
    • Sanofi-Aventis Administrative Office
• Netherlands
  • Gouda, Netherlands
    • Sanofi-Aventis Administrative Office
• Norway
  • Lysaker, Norway
    • Sanofi-Aventis Administrative Office
• Poland
  • Warszawa, Poland
    • Sanofi-Aventis Administrative Office
• Portugal
  • Porto Salvo, Portugal
    • Sanofi-Aventis Administrative Office
• Singapore
  • Singapore, Singapore
    • Sanofi-Aventis Administrative Office
• South Africa
  • Midrand, South Africa
    • Sanofi-Aventis Administrative Office
• Spain
  • Barcelona, Spain
    • Sanofi-Aventis Administrative Office
• Sweden
  • Bromma, Sweden
    • Sanofi-Aventis Administrative Office
• Switzerland
  • Geneva, Switzerland
    • Sanofi-Aventis Administrative Office
• Taiwan
  • Taipei, Taiwan
    • Sanofi-Aventis Administrative Office
• United Kingdom
  • Guildford Surrey, United Kingdom
    • Sanofi-Aventis Administrative Office
• United States
  • New Jersey
    • Bridgewater, New Jersey, United States, 08807
      • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Should fulfill the eligibility criteria for ACTIVE A or ACTIVE W trial and:

• have a systolic blood pressure of at least 110 mmHg
• not already receiving an angiotensin receptor blocking agent, unless they are willing and able to be changed to another antihypertensive agent
• no previous intolerance to angiotensin receptor blocking agents
• no proven indication for angiotensin receptor blocking agents, unless an Angiotensin Converting Enzyme (ACE) inhibitor can be substituted

Exclusion Criteria:

Patients will be excluded from ACTIVE study if any of the following are present:

• requirement for clopidogrel (such as recent coronary stent procedure)
• requirement for oral anticoagulant (such as prosthetic mechanical heart valve)
• prior intolerance to acetylsalicyclic acid (ASA) or clopidogrel
• documented peptic ulcer disease within the previous 6 months
• prior intracerebral hemorrhage
• significant thrombocytopenia (platelet count <50 x 10(9)/L)
• psychosocial reason making study participation impractical
• geographic reason making study participation impractical
• ongoing alcohol abuse
• mitral stenosis
• pregnant or nursing woman or woman of child bearing potential and not on effective birth control for at least one month prior to start of study or not willing to continue on birth control for duration of study
• severe comorbid condition such that the patient is not expected to survive 6 months
• patient currently receiving an investigational pharmacologic agent
• requirement for chronic (> 3 months) non-cyclooxygenase-2 (non-COX-2) inhibitor nonsteroidal anti-inflammatory drug (NSAID) therapy unless willing enrolled in ACTIVE A

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Irbesartan; 150 mg for 2 weeks, then up-titrated to 300 mg up to final follow-up visit	Drug: Irbesartan; oral administration (tablets) once daily; Other Names: Aprovel®
PLACEBO_COMPARATOR: Placebo; Matching placebo up to final follow-up visit	Drug: placebo; oral administration (tablets) once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke or Vascular Death as Per Adjudication	The first co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal) or vascular death - after validation by the Event Adjudication Committee (EAC).	Median follow-up of 4.5 years
First Occurence of Any Component of the Composite of Myocardial Infarction, Stroke, Vascular Death or Hospitalization for Heart Failure as Per Adjudication	The second co-primary event is the first occurence of any component of the following cluster over the duration of follow-up: myocardial infarction (nonfatal or fatal), stroke (nonfatal or fatal), vascular death or hospitalization for heart failure - after validation by the EAC.	Median follow-up of 4.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First Occurrence of Stroke	The considered event is the first occurrence of stroke (nonfatal or fatal, ischemic, hemorrhagic or of uncertain type) over the duration of follow-up, after validation by the EAC.	Median follow-up of 4.5 years
Death From Any Cause	The considered event is the death over the duration of the follow-up whatever the cause, cardiovascular or non-cardiovascular.	Median follow-up of 4.5 years
First Occurrence of Any Heart Failure (HF) Episode	The considered event is the first occurence of any HF episode defined as evidence of signs and symptoms of HF with or without hospitalization over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee).	Median follow-up of 4.5 years
First Hospitalisation for Heart Failure (HF)	The considered event is the first overnight hospital stay for HF over the duration of the follow-up, after validation by the EAC.	Median follow-up of 4.5 years
First Hospitalisation for Other Cardiovascular (CV) Cause	The considered event is the overnight hospital stay for any CV cause other than Heart Failure over the duration of follow-up, as reported by the investigator (i.e. not validated by the Event Adjudication Committee).	Median follow-up of 4.5 years

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Bristol-Myers Squibb

Publications and helpful links

General Publications

• ACTIVE I Investigators; Yusuf S, Healey JS, Pogue J, Chrolavicius S, Flather M, Hart RG, Hohnloser SH, Joyner CD, Pfeffer MA, Connolly SJ. Irbesartan in patients with atrial fibrillation. N Engl J Med. 2011 Mar 10;364(10):928-38. doi: 10.1056/NEJMoa1008816.

Study record dates

Study Major Dates

• Study Start: June 1, 2003
• Primary Completion (ACTUAL): August 1, 2009
• Study Completion (ACTUAL): August 1, 2009

Study Registration Dates

• First Submitted: November 4, 2005
• First Submitted That Met QC Criteria: November 4, 2005
• First Posted (ESTIMATE): November 7, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): October 15, 2010
• Last Update Submitted That Met QC Criteria: September 29, 2010
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Atrial fibrillation; angiotensin II blocker
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Cardiovascular Diseases; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Irbesartan
• Other Study ID Numbers: EFC4912 I; Clopidogrel (SR25990)