PPI: Ticin for the optImal anTicoagulAnt treatmeNt of Left Ventricular Thrombosis (TITAN-LVT) study

Background: Patients with left ventricular thrombosis (LVT) after acute myocardial infarction (AMI) are affected by 3-fold higher hazards of systemic embolic events (SEE), stroke and silent cerebral lesions which worsen long-term prognosis. The optimal management of this high-risk patient population has never been investigated in an adequately designed randomized trial. The current standard of care for LVT consists of vitamin K antagonists (VKA) to be continued until LVT disappears. However, a relatively high proportion of LVT patients receiving VKA still experiences thrombus persistence and recurrent ischemic events despite clinically indicated oral anticoagulation (OAC). The more favourable safety and practical profile of direct oral anticoagulants (DOACs) for patients with other clinical indications for OAC led to their off-label use also for patients with LVT. However, this treatment strategy is supported by small, observational studies and adequately powered randomized trials endorsing this emerging practice are still lacking.

Rationale: Apixaban is a DOAC which has shown to be safer and at least as effective than VKA in head-to-head studies of patients with atrial fibrillation. However, it has never been investigated in subjects with LVT. Furthermore, the optimal treatment strategy after LVT resolution is uncertain. LVT recurrence after OAC discontinuation occurs in a sizable proportion of patients (~15%) and carries an additional risk of poor prognosis. We hypothesize that Apixaban provides at least similar efficacy than VKA in terms of hard clinical events for patients with LVT with improved safety, enhanced LVT resolution and increased quality of life (QoL) and/or patient satisfaction.

Aims: (a) to collect information on the prevalence of LVT among consecutive AMI patients in Switzerland and inform on contemporary LVT predictors, (b) to investigate the role of Apixaban compared with VKA on LVT-related adverse cardiovascular events, (c) to appraise the optimal treatment combination after LVT resolution during “routine care” period; (d) to assess the effects of Apixaban versus VKA treatment on patient-reported outcomes (PROs).

Methodology: this is a prospective randomized open-label, blinded-endpoint (PROBE), investigator-initiated study of 2 x 252 subjects (i.e., 504 patients) with AMI-related LVT. Eligible patients are randomized in a 1:1 fashion to Apixaban (at the approved doses for stroke prevention in patients with atrial fibrillation) or VKA-based regimen. The study primary efficacy endpoint is the composite of all-cause death, ischemic stroke, myocardial infarction, non-central nervous system (CNS) (SEE) and major or clinically relevant non-major bleeding (BARC type 2,3 or 5 bleeding) at 6 months. The primary safety endpoint is the rate of BARC type 2,3 or 5 bleeding at 6 months. Patients will be followed for minimum 18 months after randomization or up to LVT resolution for those with thrombus persistence at 6-month follow-up. Key secondary endpoints include the incidence of LVT resolution at 6 months and PROs comprising quality of life and patient satisfaction measures. With a sample size of 504 patients, this study has an approximately 80% power to detect a non-inferiority margin of 15 days with a one-sided 2.5 alpha (restricted mean survival time analysis). Patients will be involved during the study planning and conduct in the following aspects: (a) providing advices on study design and features, (b) defining optimal measures to capture QoL and satisfaction from patient perspective, (c) to support a “patient-to-patient channel of communication” in which patients will help other subjects affected by the same disease and potentially interested in study participation explaining their experience and feelings, (d) to oversight study conduct as patient representative in the executive study committee, (e) to provide support in the interpretation and dissemination of study results.