STAT-STatin and Aspirin in Trauma

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:

1. 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.
2. 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;

1. 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.
2. 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.
3. If the study patient receives aspirin, as prescribed by their SICU attending, administration of the study drug will be stopped.
4. 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.