Apixaban Versus Warfarin in Patients With Left Ventricular (LV) Thrombus
Condition: Acute Myocardial Infarction; Left Ventricular Thrombosis; Anticoagulants and Bleeding Disorders
MeSH terms: Myocardial Infarction; Thrombosis; Hemostatic Disorders; Blood Coagulation Disorders; Infarction
Study type: Interventional
Phase: Phase 3

Summary: 
      Patients with acute ST-segment elevation myocardial infarction (STEMI) have an elevated risk
      of stroke, most of which are cardio-embolic in origin as a result of left ventricular (LV)
      thrombus formation. Anterior-wall location of a MI, in particular, can lead to the
      complications of LV aneurysm and/or thrombus, which some estimate occurs in approximately up
      to one-third of individuals within the first 2 weeks following an anterior MI.

      In the absence of anti coagulation, the risk of embolization in patients with a documented LV
      thrombus has been reported to be between 10 and 15 percent [3]. Although there are no
      randomized trials evaluating the efficacy of anticoagulation in patients with an LV thrombus
      after MI, observational studies provide substantial supporting evidence for the
      recommendation to anticoagulate patients with documented LV thrombus in order to reduce the
      risk of embolization. The observation that most events occur within the first three months
      from the MI forms the basis for the recommendation that anticoagulant therapy should be
      started early and continued for at least three to six months after myocardial infarction.
      Currently the practice guidelines recommend anticoagulation after MI only in certain settings
      such as the presence of LV thrombus or atrial fibrillation. To date there are no data on the
      use of novel oral anticoagulants (NOACS) for stroke prevention in the setting of LV thrombus
      after acute MI.

      The proposed aim of this randomized open label non inferiority clinical trial is to assess
      whether apixaban is as effective as VKA for the treatment of LV thrombus after acute ST
      segment elevation MI.

      Population: Patients with evidence of LV thrombus as assessed by trans-thoracic
      echocardiography (TTE) 3 to 7 days post admission for acute ST-elevation MI

      Intervention: The patients will be randomly assigned to treatment with apixaban or s.c
      enoxaparin 1mg/Kg BID followed by dose-adjusted warfarin to achieve a target international
      normalized ratio (INR) of 2.0 to 3.0 for 3 months.

      The study Outcomes are the presence of LV thrombus as assessed be echo, major bleeding, and
      stroke or systemic embolism and death from any cause.
    

Detailed description: 
      Background and Study Rationale:

      Patients with acute ST-segment elevation myocardial infarction (STEMI) have an elevated risk
      of stroke, most of which are cardio-embolic in origin as a result of left ventricular (LV)
      thrombus formation. The risk for stroke after myocardial infarction (MI) is estimated to be
      44-fold higher within the first 30 days, and remains 2 to 3 times higher than expected during
      the subsequent 3 years. Anterior-wall location of a MI, in particular, can lead to the
      complications of LV aneurysm and/or thrombus, which some estimate occurs in approximately up
      to one-third of individuals within the first 2 weeks following an anterior MI [2].

      In the absence of anti coagulation, the risk of embolization in patients with a documented LV
      thrombus has been reported to be between 10 and 15 percent. Although there are no randomized
      trials evaluating the efficacy of anti coagulation in patients with an LV thrombus after MI,
      observational studies provide substantial supporting evidence for the recommendation to anti
      coagulate patients with documented LV thrombus in order to reduce the risk of embolization.
      The observation that most events occur within the first three months from the MI forms the
      basis for the recommendation that anticoagulant therapy should be started early and continued
      for at least three to six months after myocardial infarction.

      Treatment of myocardial infarction has evolved dramatically in the past 20 years, and the
      vast majorities of patients undergo early coronary intervention and receive dual anti
      platelet therapy (DAPT). As a result, anterior MI alone does not warrant anti coagulation
      without evidence of LV thrombus since the combination of oral anti coagulation with DAPT
      carries an increased risk of bleeding. Practice guidelines recommend anti coagulation after
      MI only in certain settings such as the presence of LV thrombus or atrial fibrillation [5].

      Recently oral thrombin inhibitors and factor Xa inhibitors (terms as novel oral
      anticoagulants - NOACS) have been introduced for stroke prevention in patients with
      non-valvular atrial fibrillation [6-8]. These agents were shown to be at least as effective
      as Vitamin K antagonists (VKA) such as warfarin in prevention of systemic embolism, while
      having an improved safety profile with less risk of bleeding.

      To date there are no data on the use of NOACS for stroke prevention in the setting of LV
      thrombus after acute MI. Consequently, the effectiveness and safety of anti coagulation
      therapy with these novel agents in patients with LV thrombus warrants further investigation.
      The devastating impact of a stroke after an MI on morbidity and mortality, and the increasing
      number of patients at risk because of improved post-MI survival, making the goal of
      prevention of post MI stroke a major public health concern. The proposed study aims to
      address this important clinical topic.

      Objective:

      To assess whether apixaban is as effective as VKA for the treatment of LV thrombus after
      acute ST segment elevation MI.

      Design Randomized open label non inferiority clinical trial.
    

Intervention name(s): Apixaban Oral Tablet [Eliquis]; Warfarin
Intervention type(s): Drug; Drug
Intervention description(s): Apixaban 5 mg BID for 3 months. Apixaban 2.5-mg BID doses will be used in a subset of patients with two or more of the following criteria: an age of at least 80 years, a body weight of no more than 60 kg, or a serum creatinine level of 1.5 mg per deciliter (133 μmol per liter) or more. Patients with advanced renal failure (CrCl between 15 ml/min and 29 mi/min) will also receive 2.5 mg BID.; Dose-adjusted warfarin to achieve a target international normalized ratio (INR) of 2.0 to 3.0 for 3 months
Other intervention name(s): Eliquis; Coumadin
Intervention MeSH terms: Warfarin; Apixaban
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment