Clinical trial NCT03232398: Apixaban Versus Warfarin in Patients With Left Ventricular (LV) Thrombus
Official title: Apixaban Versus Warfarin in Patients With Left Ventricular (LV) Thrombus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Myocardial Infarction
Left Ventricular Thrombosis
Anticoagulants and Bleeding Disorders
Lead sponsor: Hadassah Medical Organization
Sponsor class: OTHER
First posted: 2017-07-28
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Patients with evidence of LV thrombus as assessed by trans-thoracic echocardiography
* Acute MI in last 3 months prior to enrollment

Exclusion Criteria:

* Patients with contraindications for chronic anti coagulation
* Patients with severe renal failure (CrCl\< 15 ml/min)

Primary outcomes:
measure: Presence and dimensions of Left ventricular thrombus (LV) as assessed by 2D echocardiography
timeFrame: 3 months
Secondary outcomes:
measure: Stroke or systemic embolism
timeFrame: 3 months
measure: Major bleeding
timeFrame: 3 months
measure: All cause mortality
timeFrame: 3 months
Other outcomes:
Locations:
city: Jerusalem
country: Israel
facility: Hadassah Medical Organization
Study officials:
affiliation: Hadassah Medical Organization
name: Ronny Alcalai
role: PRINCIPAL_INVESTIGATOR
References:
citation: Witt BJ, Brown RD Jr, Jacobsen SJ, Weston SA, Yawn BP, Roger VL. A community-based study of stroke incidence after myocardial infarction. Ann Intern Med. 2005 Dec 6;143(11):785-92. doi: 10.7326/0003-4819-143-11-200512060-00006.
citation: Fuster V, Halperin JL. Left ventricular thrombi and cerebral embolism. N Engl J Med. 1989 Feb 9;320(6):392-4. doi: 10.1056/NEJM198902093200610. No abstract available.
citation: Vaitkus PT, Barnathan ES. Embolic potential, prevention and management of mural thrombus complicating anterior myocardial infarction: a meta-analysis. J Am Coll Cardiol. 1993 Oct;22(4):1004-9. doi: 10.1016/0735-1097(93)90409-t.
citation: Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27.
citation: Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.