Dabigatran for the Adjunctive Treatment of Staphylococcus Aureus Bacteremia
- Conditions
- Staphylococcus Aureus EndocarditisStaphylococcus Aureus SepticemiaStaphylococcus Aureus BacteremiaStaphylococcus Aureus Bloodstream InfectionS. Aureus BacteremiaS. Aureus Bloodstream Infection
- Interventions
- Registration Number
- NCT06650501
- Lead Sponsor
- Emily McDonald
- Brief Summary
This is an open-label randomized controlled trial which will enroll patients with S. aureus bacteremia who are already taking oral anticoagulant medications (apixaban, edoxaban, or rivaroxaban) for an approved indication (stroke prevention in atrial fibrillation, prevention or treatment of venous thromboembolism). We will randomize patients to continue their existing medication or change to another medication (dabigatran) which is approved for the original indication.
Dabigatran is approved in many countries for the treatment or prevention of venous thromboembolism or preventing stroke in atrial fibrillation. Unlike the other medications listed above, dabigatran seems to have activity against S. aureus in the test tube, in animal models, and in a smaller randomized controlled trial. We wish to determine if changing to dabigratran will improve outcomes in S. aureus bacteremia in people who otherwise would have a reason to be taking it.
This study is an approved sub-study of The Staphylococcus aureus Network Adaptive Platform (SNAP) trial (NCT05137119).
If positive, this study will support a second RCT in people who do not currently have an indication for anticoagulation.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 300
- Patient is taking an oral Xa inhibitor for: stroke prevention in atrial fibrillation, treatment or secondary prevention of deep venous thrombosis or pulmonary embolism, prevention of VTE in patients who have undergone elective total hip or total knee replacement surgery provided there are 30 or more days of planned treatment remaining at the time of enrolment.
- Active bleeding (allowing up to 5 days from the index blood culture to randomize in the event anti-thrombotic therapy is resumed)
- Anticipated major cardiac surgery, neurosurgery, or spine surgery within the next 3 days
- Pregnancy
- Known use of dabigatran within last month
- Allergy to dabigatran
- Concomitant use of amiodarone, ketoconazole, rifampin, verapamil, clopidogrel, prasugrel, or ticagrelor
- eGFR < 30mL/minute calculated by Cockcroft-Gault equation using adjusted weight [if acute kidney injury can allow for up to 5 days from index blood culture to allow for recovery]
- Off label use (e.g., metallic mechanical heart valve, left ventricular thrombus, antiphospholipid antibody syndrome)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Continue current anticoagulant edoxaban Patients will continue their currently prescribed apixaban, edoxaban, or rivaroxaban Continue current anticoagulant Rivaroxaban Patients will continue their currently prescribed apixaban, edoxaban, or rivaroxaban Change to Dabigatran Dabigatran Patients will have their anticoagulation changed to dabigatran at the monograph approved dose for the indication, bleeding risk, and renal function. Continue current anticoagulant Apixaban Patients will continue their currently prescribed apixaban, edoxaban, or rivaroxaban
- Primary Outcome Measures
Name Time Method Desirability of Outcome Ranking (DOOR) Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) Desirability of Outcome Ranking (DOOR) - an ordinal outcome with 5 levels defined:
Rank 1 - Alive without complication Rank 2 - Alive with 1 complication Rank 3 - Alive with 2 complications Rank 4 - Alive with 3 complications Rank 5 - Dead
Complications include:
1. Clinical failure: Absence of resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated.
2. Infectious Complications: Including new endocarditis; new evidence of other deep metastatic foci (e.g., osteomyelitis or deep abscess); relapse of MRSA bacteremia after a patient has sterilized their initial blood cultures; readmission for subsequent care of S. aureus bacteremia; need for unplanned source control procedures
3. Serious adverse drug event (Common Terminology Criteria class 4) due to study drug OR adverse drug event (classes 1-3) leading to discontinuation of the study drug
- Secondary Outcome Measures
Name Time Method Clinical failure Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) Defined as the absence of resolution of clinical signs and symptoms of S. aureus bacteremia such that no additional antibiotic therapy is required or anticipated for its treatment.
Serious Adverse Event or Adverse Event Leading to Discontinuation Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) Defined as a serious adverse drug event (Common Terminology Criteria for Adverse Events (CTCAE) class 4) presumed due to study drug OR adverse drug event (CTCAE classes 1-3) leading to discontinuation of the study drug
All cause mortality Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) Death from any cause
Infectious Complications Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) Defined as change in therapy for inadequate clinical response; new endocarditis; new evidence of other deep metastatic foci (e.g., osteomyelitis or deep abscess); relapse of MRSA bacteremia after a patient has sterilized their initial blood cultures; readmission for subsequent care of S. aureus bacteremia; need for unplanned source control procedures. New implies that the complication was not suspected at enrollment and is not a function of delay to diagnostic testing.
Clinically relevant major bleeding Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) This will be defined according to the criteria of the International Society on Thrombosis and Haemostasis as one or more of the following: fatal bleeding; symptomatic bleeding in a critical area or organ (including hemorrhagic stroke); bleeding that causes a fall in hemoglobin level of ≥20 g/L; or bleeding that requires a transfusion of 2 or more units of whole blood or red cells. For bleeds into non-critical areas, we will also record the site of bleeding.
Clinically relevant venous thromboembolic events Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) This will be defined as an acute objectively confirmed deep vein thrombosis (upper extremity, lower extremity, other such as portal vein, cerebral vein, splanchnic vein) and/or segment or proximal pulmonary embolism, which is symptomatic and/or necessitates specific treatment. Below knee DVT and superficial thrombophlebitis are not included. Pulmonary embolism needs to be, segmental or proximal. Subsegmental pulmonary embolisms are not included as they have poor interrater reliability and may represent artefact in up to 50% of cases.
Clinically relevant stroke Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) Stroke is defined as the acute onset of focal neurological dysfunction caused by brain, spinal cord, or retinal vascular injury because of infarction (ischemia). Ideally, at least one of the following should be present to confirm the diagnosis of stroke: confirmation by neurology, stroke specialist, or neurosurgical specialist, brain imaging (e.g., CT scan, MRI scan, or cerebral vessel angiography compatible with acute ischemia). If the acute focal signs represent a worsening of a previous deficit, these signs must persist for more than 24 hours and be accompanied by an appropriate new MRI or CT scan finding. In the absence of neuroimaging, a staff neurologist consult which makes the diagnosis of stroke will be considered.
Clinically relevant acute myocardial infarction Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) Patients with S. aureus bacteremia often have substantial physiological stresses which can be associated with rises in cardiac troponin (demand ischemia). For the purposes of this outcome, acute myocardial infarction is captured as a type 1 myocardial infarction: detection of rise and/or fall of cardiac biomarkers with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia. For the purposes of this pragmatic trial, such a myocardial infarction will be inferred from the opinions of the staff cardiologist, intensivist, or general internal medicine specialist. The peak troponin value will be recorded, and a redacted copy of the relevant consultant's note and ECGs will be uploaded for audit.
Clinically relevant arterial thromboembolic event Day 90 post enrollment in the S. aureus Network Adaptive Platform Trial (NCT05137119) Clinical history compatible with sudden worsening of end organ or limb perfusion and confirmation by imaging (e.g., CT angiography, arterial doppler) or need for urgent surgery or thrombolysis.
Trial Locations
- Locations (1)
McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital)
🇨🇦Montreal, Quebec, Canada