STAT-STatin and Aspirin in Trauma

Study Overview
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Brief Summary
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This is a phase II, pragmatic, prospective, randomized, double-blind, adaptive clinical trial examining the efficacy of statins and aspirin in the reduction of acute lung injury and venous thromboembolism in patients with fibrinolysis shutdown.

Detailed Description
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This protocol describes a Phase II, pragmatic, prospective, randomized, double-blind, adaptive clinical trial comparing combination rosuvastatin and aspirin therapy to placebo. Currently, there is no treatment for fibrinolysis shutdown or effective measures to prevent macro- and micro-thrombosis post-injury, thus, placebos are acceptable as the control group. Treatment for both groups would otherwise be by standard of care, which includes pharmacologic thromboembolism prophylaxis. The safety of concomitant use of VTE pharmacological prophylaxis with statins and aspirin is well documented in cardiac surgery patients. Eligible adult patients with anticipated ICU admission will be screened for eligibility in the STAT trial (see inclusion/exclusion criteria) based on history, physical exam and clinical data obtained during their initial treatment. If deemed eligible for enrollment in the STAT trial, the patient, their legally authorized representative (LAR), or their proxy decision-maker will be contacted by our on-site professional research assistants (PRAs) for consent to enroll in the study. Only patients for whom consent is obtained within 24 hours post-injury will be eligible for randomization into the treatment phase of the study. Upon consent, blood samples will be obtained immediately after consent at 6, 12, 24, 48, 72, 120 and 168 hours after injury. Traditional and tPA-Challenge TEG will be performed on these samples to evaluate the development of the three fibrinolysis phenotypes. Upon receiving an order for prophylactic anticoagulation, the DHMC pharmacy will randomize the patient to the control or intervention arms of the study. Randomization will occur using a computer-generated block (groups of 20 patients) random number sequence in sealed, opaque envelopes maintained at the DHMC pharmacy. Patients assigned to the intervention arm will receive the standard of care anticoagulation plus the combination experimental drugs (20mg of rosuvastatin daily and 325mg of aspirin) daily either orally or crushed via feeding tube. These doses are consistent with those currently recommended in the postoperative period following cardiac surgery. Patients assigned to the control group will receive identical-looking placebos at the same time points as the experimental group either orally or crushed via feeding tube. Healthcare providers, PRAs and patients will be blinded to study allocation standard of care anticoagulation plus the combination placebos (produced to look and group assignment (double-blind design). The DHMC pharmacist will be aware of the patient's treatment arm so that rapid un-blinding will be possible in the event of an adverse event possibly related to a study medication. The blood samples will be used to monitor for the type of fibrinolysis, the function of the biochemical mediators of coagulation and potential side effects of these medications, as explained in more detail below. Study medications or placebo will be administered during ICU admission while patients are receiving the standard of care dosing of prophylactic anticoagulation (i.e. heparin or heparin-derivatives) and will be interrupted concomitantly with interruption of pharmacological VTE prophylaxis. Patients diagnosed with VTE will be withdrawn from the study drugs and will receive the appropriate VTE treatment per current ICU protocols. The investigators will monitor function/damage of liver, renal and muscle before initiation of therapy (if the patient already has a recent test of these functions up to 12 hours prior to the initiation of therapy, the result of this test will be used to avoid unnecessary sampling), and upon the end of the therapy or as clinically necessary (i.e., any clinical indications of organ dysfunction). Stopping rules are: Bleeding: Any ongoing bleeding requiring blood transfusion or operative procedure to stop bleeding. Bleeding will be monitored via monitoring of the daily measurements of hemoglobin levels, which are an integral part of the ICU protocols for trauma patients. Study medications will be unblinded and stopped if there is an unexplained drop in hemoglobin level greater than 2g/dl within 24 hours after enrollment leading to discontinuation of VTE Prophylaxis OR a drop in hemoglobin level greater than 1g/dl daily for three consecutive days leading to discontinuation of VTE Prophylaxis. Liver dysfunction: Alteration in liver chemistry is a rare sequela of statin therapy. A meta-analysis of 13 placebo-controlled trials incorporating nearly 50,000 patients examined the incidence of liver toxicity (defined as elevation of hepatic transaminases greater than 3 times the upper limit of normal) in patients receiving statin therapy. 77 This study reported the incidence of elevated AST or ALT in statin-treated patients vs placebo controls as 1.14% and 1.05%, respectively (OR 1.25; 95% CI 0.99 - 1.62). Further, the only individual drug associated with a statistically significant elevation in transaminases over a follow-up interval exceeding 3 years was fluvastatin. These and more recent data have informed expert opinion, 78 which ultimately prompted the FDA in 2012 to revoke the recommendation that liver function tests be monitored in patients taking statins. That said, given our at-risk patient population, the investigators will use the accepted definition of 3 times the baseline of the AST test as the criterion for interruption of therapy; Renal dysfunction: While transient proteinuria has been observed in patients undergoing statin therapy, acute kidney injury (AKI) is a rare complication. The JUPITER randomized controlled trial incorporating approximately 17,000 patients and comparing rosuvastatin to placebo found no difference in AKI (6.0% v 5.4%; p = 0.08) between the groups. 79 In a randomized trial comparing rosuvastatin to atorvastatin, simvastatin, and pravastatin, acute renal failure was observed in 2 of 420 patients receiving high-dose rosuvastatin. 80 The AKI as serum creatinine increase greater than 2x of baseline (>Grade 1, based on AKIN criteria) as the criterion to interrupt therapy. Muscle injury: Myositis and rhabdomyolysis are rare sequelae of statin therapy. A meta-analysis of 26 studies incorporating nearly 130,000 patients identified an incidence of between 1 and 4 per 10,000 patients developing rhabdomyolysis following statin therapy. 81 This meta-analysis includes a study of 12,000 patients comparing the efficacy of simvastatin 80mg with 20mg doses. In this study, the overall incidence of myolysis and rhabdomyolysis were 0.5 and 0.1 per 1000 person-years, respectively, wherein all cases of rhabdomyolysis occurred in the high dose cohort. 82 The accepted definition of myositis is muscle pain in the setting of a serum creatine kinase concentration greater than 10 times the patient's baseline.46 The investigators will use this threshold to clinically quantify myositis, preceding potential development of rhabdomyolysis, as well as the criterion to interrupt therapy. If the study patient receives aspirin, as prescribed by their SICU attending, administration of the study drug will be stopped. Thrombocytopenia: If the study patient's platelet count decreases below 50,000 uL requiring transfusion of platelets while receiving the study drug, administration of the study drug will be stopped. This will be monitored and recorded in our twice daily safety monitoring log. Any of the above-mentioned stopping rules will be reported as an SAE and will trigger an immediate review by the DSMB.

Official Title
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STAT (STatins and Aspirin in Trauma) Trial: A Phase II, Pragmatic, Prospective, Randomized, Double-blind, Adaptive Clinical Trial Examining the Efficacy of Statins and Aspirin in the Reduction of Acute Lung Injury and Venous Thromboembolism in Patients With Fibrinolysis Shutdown

Conditions
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Wounds and Injuries, Venous Thromboembolism

Intervention / Treatment
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* Drug: Aspirin and Rosuvastatin
* Drug: Placebo (for Aspirin and Rosuvastatin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: all adult trauma patients requiring admission to the surgical intensive care unit (SICU) and expected hospital stay for at least 3 days. Outside hospital transfer patients that require SICU admission less than 24 hours after their injury are also eligible for enrollment. Exclusion criteria for prophylactic anticoagulation and for the study are: Known inherited bleeding disorder or coagulopathy Known contraindication to pharmacologic anticoagulation Spinal column fracture with epidural hematoma Head trauma/central nervous system injury Severe TBI; defined as AIS Head >3 Intracranial hemorrhage; subdural or epidural hematoma Neurosurgery service objection; neurosurgical contra-indications will be documented Ongoing hemorrhage requiring blood product transfusion Thrombocytopenia (platelet count < 50,000) Non-operatively managed liver or spleen injuries Grade III or above Known chronic kidney disease (GFR < 15ml/min) Rising creatinine (Cr > 1.5x baseline) at the time of enrollment Inclusion in any other clinical trial Documented previous ischemic strokes In addition, the following exclusion criteria apply: Receiving statin or aspirin therapy pre-injury, as potentially being assigned for Control would increase patient's risks Known allergy or other contraindication to statins or aspirin Pregnant patients Prisoners, as their ability to freely consent is impaired Inability to obtain consent from patient or proxy prior to 48 hours post-injury VTE event (DVT or PE) diagnosed during current hospitalization prior to obtaining informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>Administration of 325mg Aspirin and 20mg of Rosuvastatin mixture in a single capsule daily either orally or via a feeding tube for the duration of the patient's stay in the ICU. | Drug: Aspirin and Rosuvastatin<br>* Patients assigned to the intervention arm will receive the standard of care anti-coagulation plus the combination experimental drugs (20mg of rosuvastatin daily and 325mg of aspirin) daily either orally or via feeding tube.<br>|
| Placebo Comparator: Control<br>Administration of the placebo, which is identical-looking to the Aspirin and Rosuvastatin single capsule mixture, daily either orally or via a feeding tube for the duration of the patient's stay in the ICU. | Drug: Placebo (for Aspirin and Rosuvastatin)<br>* Patients assigned to the control group will receive the standard of care anti-coagulation plus identical-looking placebos either orally or via feeding tube.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of VTE | Based on screening duplex ultrasound (US) of legs and central line on day 5 or upon ICU discharge or upon symptoms of VTE (whichever comes first). | Day 5 or ICU discharge or upon symptoms of VTE (whichever comes first) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fibrinolysis Phenotypes | Measured by traditional and tissue plasminogen activator (tPA) - Challenge thrombelastography (TEG) lysis at 30 minutes (LY30). | During ICU stay at the following timepoints - 6, 12, 24, 48, 72, 120 and 168 hours | 
| Plasminogen Activator Inhibitor (PAI) - 1 and Tissue Plasminogen Activator (tPA) Levels in Plasma | To be measured in platelet poor plasma (PPP) | During ICU stay at the following timepoints - 6, 12, 24, 48, 72, 120 and 168 hours | 
| Incidence of Acute Lung Injury (ALI) | Based on Berlin Criteria | Within two weeks post-injury | 
| Ventilator Free Days | As measured by ventilator-free days (VFD). VFDs are typically defined as follows (1): VFDs = 0 if subject dies within 28 days of mechanical ventilation. VFDs = 28 - x if successfully liberated from ventilation x days after initiation. VFDs = 0 if the subject is mechanically ventilated for >28 days. | Up to 28 days | 
| Incidence of Arterial Thrombotic Complications: Myocardial Infarction (MI) and Cerebrovascular Accident (CVA). | MI and CVA were diagnosed by health care providers and documented in the EMR. | Up to 28 days | 
| All-cause Mortality | Mortality due to any cause was assessed. | 30 days | 
| Intensive Care Unit (ICU) Days | ICU-free days will be calculated based on (28 - number of days spent in the ICU) formula | 28 days | 
| Incidence of Multiple Organ Failure (MOF) | As measured by Denver MOF score, which grades (from 0-3, with 3 indicating worst dysfunction) four organ systems (lung, kidney, liver, heart), thus varying from 0 to 12 (worst possible dysfunctions) and defines MOF as score > 3. | Up to 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fibrinolysis