Evaluation of Fondaparinux in Patients With a Heart Rhythm Disturbance Who Undergo Restoration of Normal Heart Rhythm

An International, Multicentre, Randomised, Open, Controlled, Two-parallel Group, Phase II Pilot Study to Evaluate the Efficacy and Safety of ARIXTRA™ for Anticoagulation of Patients With Atrial Fibrillation Undergoing Electric Cardioversion Following Transesophageal Echocardiography

The purpose of this study is to test whether Fondaparinux is effective and safe to prevent thromboembolic events (like for example strokes) and bleeding events in patients who undergo a normalisation of their heart rhythm disturbance. Fondaparinux will be compared with Heparin and tablets containing Vitamin-K-Antagonists (Phenprocoumon, Fluindione, or Warfarin).

Study Overview

• Status: Completed
• Conditions: Fibrillation, Atrial
• Intervention / Treatment: Drug: fondaparinux; Drug: unfractionated heparin; Drug: Vitamin-K-Antagonist

• Study Type: Interventional
• Enrollment (Actual): 349
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Albi, France, 81000
    • GSK Investigational Site
  • Antony cedex, France, 92166
    • GSK Investigational Site
  • Brest Cedex, France, 29609
    • GSK Investigational Site
  • Créteil, France, 94000
    • GSK Investigational Site
  • Evecquemont, France, 78740
    • GSK Investigational Site
  • Montpellier Cedex 5, France, 34295
    • GSK Investigational Site
  • Paris cedex 12, France, 75571
    • GSK Investigational Site
  • Paris cedex 13, France, 75651
    • GSK Investigational Site
  • Pau, France, 64046
    • GSK Investigational Site
  • Pessac cedex, France, 33604
    • GSK Investigational Site
  • Poitiers cedex, France, 86021
    • GSK Investigational Site
  • Rennes Cedex 9, France, 35033
    • GSK Investigational Site
  • Toulouse Cedex 09, France, 31059
    • GSK Investigational Site
  • Toulouse cedex 3, France, 31076
    • GSK Investigational Site
• Germany
  • Berlin, Germany, 13353
    • GSK Investigational Site
  • Berlin, Germany, 10249
    • GSK Investigational Site
  • Berlin, Germany, 10405
    • GSK Investigational Site
  • Baden-Wuerttemberg
    • Freiburg, Baden-Wuerttemberg, Germany, 79106
      • GSK Investigational Site
  • Bayern
    • Aschaffenburg, Bayern, Germany, 63739
      • GSK Investigational Site
    • Bad Toelz, Bayern, Germany, 83646
      • GSK Investigational Site
    • Simbach a. Inn, Bayern, Germany, 84359
      • GSK Investigational Site
  • Brandenburg
    • Potsdam, Brandenburg, Germany, 14467
      • GSK Investigational Site
  • Hessen
    • Frankfurt, Hessen, Germany, 60488
      • GSK Investigational Site
    • Kassel, Hessen, Germany, 34121
      • GSK Investigational Site
    • Kassel, Hessen, Germany, 34125
      • GSK Investigational Site
  • Mecklenburg-Vorpommern
    • Hagenow, Mecklenburg-Vorpommern, Germany, 19230
      • GSK Investigational Site
  • Nordrhein-Westfalen
    • Bielefeld, Nordrhein-Westfalen, Germany, 33604
      • GSK Investigational Site
    • Bonn, Nordrhein-Westfalen, Germany, 53127
      • GSK Investigational Site
    • Bonn, Nordrhein-Westfalen, Germany, 53115
      • GSK Investigational Site
    • Duisburg-Huckingen, Nordrhein-Westfalen, Germany, 47259
      • GSK Investigational Site
    • Unna, Nordrhein-Westfalen, Germany, 59423
      • GSK Investigational Site
    • Wesel, Nordrhein-Westfalen, Germany, 46483
      • GSK Investigational Site
  • Sachsen
    • Pirna, Sachsen, Germany, 01796
      • GSK Investigational Site
  • Sachsen-Anhalt
    • Magdeburg, Sachsen-Anhalt, Germany, 39120
      • GSK Investigational Site

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:

• Male or female patients aged at least 18 years with atrial fibrillation (AF) meeting at least one of the following criteria (a, b, c): a. Acute clinical symptoms (like palpitations, chest pain, dyspnea, fatigue, lightheadedness, or syncope) for at least 48 hours and AF on baseline ECG b. Newly discovered AF persisting for >=7 days c. Recurrent AF persisting for >=7 days

Exclusion Criteria:

• No documented sinus rhythm on ECG for more than 1 year
• Acute neurological deficits (TIA, stroke, intracranial bleeding), or known disease which may cause neurological deficits (e.g., multiple sclerosis, seizure disorder)
• Treatment with antithrombotic agents, including low-dose anticoagulation, for more than 48 hours prior to randomisation
• Treatment with oral NSAIDs or ASA at doses greater than 325 mg per day for more than 72 hours prior to randomisation
• Anticoagulant therapy required or likely to be required during the study period
• Treatment with ASA at a dose greater than 325 mg per day or oral NSAIDs (at any dose) required or likely to be required during the study period
• Treatment with two or more antiplatelet agents (e.g. clopidogrel and ASA) at any dose at the same time (i.e., within 24 hours)
• Known hypersensitivity to UFH, VKA, or Fondaparinux or one of these drugs' excipients
• Active, clinically significant bleeding or clinically significant bleeding within the past month
• Major surgery within the previous three months
• Uncontrolled arterial hypertension (persistent systolic blood pressure over 180 mm Hg or diastolic blood pressure over 110 mm Hg)
• Bacterial endocarditis
• Calculated creatinine clearance < 30 mL/min
• Body weight < 50 kg
• Planned surgery or intervention within the next 65 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• 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: fondaparinux	Drug: fondaparinux; Comparison of different drugs
Active Comparator: Arm 2: unfractionated heparin + Vitamin-K-Antagonist	Drug: unfractionated heparin; Comparison of different drugs; Drug: Vitamin-K-Antagonist; Comparison of different drugs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With at Least One Event of Cerebral Neurologic Event, Systemic Thromboembolism, Death From Any Cause, and/or Major Bleeding Until the End of Treatment (EOT) Plus 4 Days	Cerebral neurologic events are defined as any new neurologic disorders caused by cerebrovascular embolization, e.g., Transient Ischemic Attack (TIA), cerebral infarction. The cerebrovascular origin of the event has to be confirmed by objective procedures. Systemic thromboembolism comprises any arterial thromboembolic event (e.g., peripheral vascular embolism, mesenteric infarct, or myocardial infarction). All cerebral neurologic events were adjudicated by a Central Adjudication Committee (CAC), members of which were unaware of the participants' treatment assignment.	Baseline (Day 1) until Day 64 (4 days after the EOT [i.e., last administration of study drug]) for CP participants; Baseline until Day 36 (4 days after the EOT) for CN participants

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Thrombus-negative and Thrombus-positive Participants (Par.) With at Least One Cerebral Neurologic Event	Cerebral neurologic events are defined as any new neurologic disorders caused by cerebrovascular embolisation, e.g., TIA, cerebral infarction. All cerebral neurologic events were adjudicated by a CAC, members of which were unaware of the participants' treatment assignment.The cerebrovascular origin of the event was confirmed by objective procedures. A thrombus or blood clot is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system (i.e., clotting factors).	Baseline (Day 1) until Day 64 (4 days after the EOT [i.e., last administration of study drug]) for CP participants; Baseline until Day 36 (4 days after the EOT) for CN participants; and from Baseline until the follow-up visit (FU) (Day 90+/-7)
Number of Thrombus-negative and Thrombus-positive Participants With at Least One Systemic Thromboembolism	Systemic thromboembolism comprises any arterial thromboembolic event (e.g., peripheral vascular embolism, mesenteric infarct, or myocardial infarction). All systemic thromboembolic events were adjudicated by a CAC, the members of which were unaware of the participants' treatment assignment. A thrombus or blood clot is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system (i.e., clotting factors).	Baseline (Day 1) until Day 64 (4 days after the EOT [i.e., last administration of study drug]) for CP participants; Baseline until Day 36 (4 days after the EOT) for CN participants; and from Baseline until the follow-up visit (FU) (Day 90+/-7)
Number of Thrombus-negative and Thrombus-positive Participants Who Died From Any Cause	The cause of death was classified as due to a thromboembolic event (like cerebral infarction), bleeding, or other established diagnosis, or as unexplained. All deaths were adjudicated by an independent CAC, the members of which were unaware of the participants' treatment assignment. A thrombus or blood clot is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system (i.e., clotting factors).	Baseline (Day 1) until Day 64 (4 days after the EOT [i.e., last administration of study drug]) for CP participants; Baseline until Day 36 (4 days after the EOT) for CN participants; and from Baseline until the follow-up visit (FU) (Day 90+/-7)
Number of Thrombus-negative and Thrombus-positive Participants With at Least One Major Bleeding Event	Major bleeding: fatal, and/or symptomatic in a critical area/ organ, causes a fall in hemoglobin of >=3 grams/deciliter compared with the pre-randomization level, or leads to the transfusion of >=2 units of whole blood/red blood cells. All bleeding events were adjudicated by a CAC, the members of which were unaware of the participants' treatment assignment. A thrombus/ blood clot is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets, and the activation of the humoral coagulation system (i.e., clotting factors).	Baseline (Day 1) until Day 64 (4 days after the EOT [i.e., last administration of study drug]) for CP participants; Baseline until Day 36 (4 days after the EOT) for CN participants; and from Baseline until the follow-up visit (FU) (Day 90+/-7)
Number of Thrombus-negative and Thrombus-positive Participants With at Least One Minor Bleeding Event	Minor bleeding is defined as clinically overt bleeding events that do not meet the criteria for major or clinically relevant non-major bleeding. All episodes of bleeding were adjudicated by an independent CAC, the members of which were unaware of the participants' treatment assignment.	Baseline (Day 1) until Day 64 (4 days after the EOT [i.e., last administration of study drug]) for CP participants; Baseline until Day 36 (4 days after the EOT) for CN participants; and from Baseline until the follow-up visit (FU) (Day 90+/-7)
Number of Participants With Primary Successful Electrical Cardioversion (CV) in Sinus Rhythm	CV may be performed electively to restore sinus rhythm in patients with persistent AF. The primary successful electric CV was assessed by a 12- lead electrocardiogram (ECG) directly after the CV. Results of the last cardioversion were used in cases for which more than one CV was performed.	Day 1 until Day 3
Number of Participants With a Thrombus in the Left Atrium (LA) or in the Left Atrial Appendage (LAA) at the Time of the Second TEE	Atrial fibrillation (AF) causes stagnant blood in the LA or LAA and can lead to a thromboembolism. Stasis in the LAA represents the principal mechanism of thrombus formation in AF.	At second TEE (at Day 28+/-4)
Number of Thrombus-negative and Thrombus-positive Participants With Conversion to Sinus Rhythm	Sinus rhythm is the normal beating of the heart, as measured by an ECG. Normal sinus rhythm not only indicates that the rhythm is normally generated by the sinus node and is traveling in a normal fashion in the heart, but it also indicates that the heart rate (the rate at which the sinus node is generating impulses) is within normal limits.	Baseline (Day 1) until Day 64 (4 days after the EOT [i.e., last administration of study drug]) for CP participants; Baseline until Day 36 (4 days after the EOT) for CN participants; and from Day 64 until the follow-up visit (FU) (Day 90+/-7)
Number of Participants Who Were Re-hospitalized	Hospitalization signifies that the participant has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician's office or out-patient setting. Re-hospitalization refers to an event of hospitalization after discharge for the initial hospitilization for the cardioversion.	Baseline (Day 1) until Day 64 (4 days after the EOT [i.e., last administration of study drug]) for CP participants; Baseline until Day 36 (4 days after the EOT) for CN participants; and from Baseline until the follow-up visit (FU) (Day 90+/-7)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start: August 1, 2009
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: May 28, 2009
• First Submitted That Met QC Criteria: May 28, 2009
• First Posted (Estimate): June 1, 2009

Study Record Updates

• Last Update Posted (Estimate): October 1, 2012
• Last Update Submitted That Met QC Criteria: September 20, 2012
• Last Verified: September 1, 2012

More Information

Terms related to this study

• Keywords: Pathologic Processes; Atrial Fibrillation; Cardiovascular Diseases; Heart Diseases; Anticoagulants; Arrhythmias, Cardiac; Cardioversion, Electric; Pathological Conditions, Sings and Symptoms
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Micronutrients; Vitamins; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Heparin; Calcium heparin; Fondaparinux; PENTA
• Other Study ID Numbers: 111418