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
Phase: PHASE2
Conditions: Wounds and Injuries, Venous Thromboembolism
Sponsor: Denver Health and Hospital Authority

 
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COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490   TELEPHONE:  303-724-1055 Fax:  303-724-0990 
 
Protocol #:  16-0391 
Project Title: 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. 
 
Principal Investigator: E. E. Moore, MD  
Version Date:  02/22/2019 
 
I. Hypothesis and Specific Aims: 
 
Patients sustaining life-threatening injuries are at high risk for thrombotic events both at the macro level such 
as venous thromboembolic (VTE) events as well as at the microvascular level leading to pulmonary 
dysfunction (acute lung injury or ALI and adult respiratory distress syndrome or ARDS).1, 2 These 
complications have been traditionally attributed to an unbalance in injury induced inflammatory processes 
but recent investigations have suggested that hypercoagulation is a contributing mechanism. 3    Emerging 
evidence has indicated that, in contrast to rapid clot formation, early post-injury resistance to clot degradation 
(resistance to fibrinolysis or fibrinolysis shutdown) may play a significant mechanistic role in trauma-induced 
coagulopathy (TIC) and its sequelae.4, 5 
A recent pilot study in cardiac surgery patients suggested that while coagulation activity was increased and 
more fibrin was formed immediately postoperatively in patients who subsequently developed ALI, there was 
insufficient fibrinolytic activity to remove the increased amount of fibrin.6 Fibrin degradation is modulated by 
plasminogen and plasminogen-activator-inhibitor-1 (PAI-1). 3 PAI-1 is the major inhibitor of two plasminogen 
activators, namely, urokinase-type plasminogen activator (u-PA), which activates fibrinolysis at the tissue 
level, and tissue-type plasminogen activator (t-PA), which activates intravascular fibrinolysis. 7 
Trauma and surgery patients do present increased levels of PAI-1, which correlated with the subsequent 
development of organ failure, such as ALI and ARDS. 2 Platelets play a role in both VTE and lung injury, thus 
anti-platelet agents (such as aspirin) have been increasingly used in populations at-risk for thrombotic 
complications, including trauma patients. 1, 3, 8, 9 
Statins and aspirin have been proposed and studied as potential therapeutic agents that can block the 
above described prothrombotic mechanisms.3, 10, 11  Current guidelines for cardiac surgery patients 
recommend the use of aspirin and statins as safe and effective agents to reduce thrombotic complications. 12 
The comparison between cardiac surgery  patients  and  trauma  patients is  pertinent, as  major  
surgical procedures are often labeled as “schedule trauma” or “controlled injury” (see NIGMS PAR at 
http://grants.nih.gov/grants/guide/pa-files/PAR-13-291.html and Silliman et al. 13). Specifically in healthy 
individuals (as the majority of trauma patients), the large JUPITER trial has convincingly demonstrated a 
reduction in the incidence of VTEs with the use of statins (rosuvastatin). 14 
Currently, there are no pharmacologic interventions in use in the intensive care unit (ICU) setting to treat 
resistance to fibrinolysis (shutdown). Moreover, current interventions have not been successful in further 
reducing thrombotic complications such as VTE and lung injury in trauma and surgical patients.   1,  15 
Therefore, we hypothesize that rosuvastatin and aspirin (ASA), two FDA-approved medications, will 
reduce the development of venous thromboembolism by modifying both the platelet- and endothelial-derived 
fibrinolytic regulators contributing to fibrinolysis shutdown. 
The primary objective of this study is to evaluate the efficacy of combination of rosuvastatin and aspirin in 
the reduction of the incidence of VTE (i.e. pulmonary embolism and deep venous thrombosis) in critically ill 
trauma patients. 
As a secondary objective, we propose to evaluate the efficacy of rosuvastatin and aspirin in the incidence 
of ALI (as measured by the Berlin criteria16) and on ventilator days (as measured by ventilator-free days) in 
critically ill trauma patients. Another secondary objective is to evaluate the efficacy of rosuvastatin and 
aspirin on reducing other adverse outcomes in critically ill trauma patients (30-day mortality, ICU days, 
and arterial thrombosis such as myocardial infarction, MI and stroke). In addition, we will further explore 
the mechanisms through which these agents influence the coagulation cascade in patients at-risk for 
thrombotic complications (fibrinolysis phenotypes incidence, systemic PAI-1 and tPA levels). 
This protocol describes a Phase II, pragmatic, prospective, randomized, double-blind, adaptive clinical trial 
comparing rosuvastatin and aspirin (in combination) to placebo. 
 

 
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II. Background and Significance: 
 
Trauma is the leading cause of death for individuals in the first four decades of life in the United States. 
17 The majority of these deaths occur within just a few hours following injury.18   Patients surviving the initial 
insult remain at risk of death due to either macro-vascular (VTE) or micro-vascular (ALI, ARDS) thrombotic 
complications.18 Recent investigations into post-trauma care have focused on the reduction of the 
hypercoagulability component of trauma-induced coagulopathy.19  This work has concentrated on 
understanding the mechanisms behind large vein thrombosis in an effort to reduce the risk of VTE events. 
Geerts et al. studied 350 critically injured patients and found that greater than 50% had evidence of DVT 
based upon venography screening.20    Based upon these background data, they conducted a randomized 
study comparing unfractionated versus fractionated heparin as prophylaxis against DVT.  They found that 
heparin decreased the incidence by 19%, while low molecular weight heparin (LMWH) therapy decreased 
the incidence by 43%.21   Other groups, including ours, have shown that less rigorous screening and use of 
LMWH can reduce the incidence of venous thrombi to rates ranging from 2.5-9%.22-24   Despite this and other 
extensive work, pulmonary embolism (PE) remains one of the most common causes of post-injury mortality 
and has been associated with up to 12% of late trauma-related deaths.25     Furthermore, these deaths 
continue to occur in the setting of pharmacological and mechanical prophylactic therapies, the current 
standard of VTE-prevention care. 26 
Postinjury micro-thrombosis may manifest as distant organ dysfunction or postinjury multiple organ 
failure, including ALI and ARDS.27, 28 The pulmonary system is nearly always the first to exhibit dysfunction. 
29 Overall, these patients spend an average of 20 days on the ventilator with an average hospital-stay 
greater than 30 days.30   The mechanism of post-trauma ALI remains unclear and is most likely multifactorial. 
However, trauma-induced coagulopathy (TIC) has been suggested to play a significant role in the 
development of secondary pulmonary pathology.31 
The first investigations linking coagulation dysfunction and ALI were performed by Hardaway, et al. in 
the 1960s and 1970s. 32-34 This group found that hypercoagulability and resistance to clot breakdown 
(fibrinolysis shutdown) developed in trauma patients following hemorrhagic shock and resuscitation.  They 
proposed that these factors predispose the trauma patient to microvascular thrombosis of the pulmonary 
system, resulting in ALI. 33, 34   Based upon this hypothesis, they conducted a phase II clinical trial evaluating 
the efficacy of tissue plasminogen activator (tPA; a blood protein that activates fibrinolysis, commonly used 
in MI and stroke patients to dissolve life-threatening occlusive clots) on pulmonary function in trauma 
patients  when  administered  within  48  hours  of  injury.35        Though  this  trial  had  promising  results, 
administration of systemic tPA remains high-risk following trauma and major surgery and is contraindicated 
in the setting of neurosurgery.  Furthermore, tPA has been shown to act on neuronal receptors and has been 
linked to excitotoxicity and subsequent cell death.36   As such, the use of tPA in trauma patients, particularly 
those having sustained head injury, remains controversial and has seen little clinical use given the 
appreciable risks of ongoing bleeding, secondary bleeding and potential neurologic sequelae. 
While VTE is related to venous macrovascular insult and ALI to arteriolar microvascular thrombosis, 
review of the existing literature engenders the concept that post-trauma ALI and VTE are manifestations of 
the same pathologic process, both a hyper-coagulable and fibrinolysis resistant state. 31, 37  Currently, there 
are no clinical methods to measure and quantify microvascular occlusion.  However, animal models have 
been employed to demonstrate microthrombi within the pulmonary vascular beds resulting in foci for 
leukocyte-induced  lung  injury38   which  can  be  attenuated  with  pharmacologic  thrombolytic  therapy.39 
However, as previously discussed, the use of thrombolytics, such as tPA, is high-risk and controversial in a 
post-trauma patient already predisposed to bleeding. 
We propose that there is a missing component in the understanding of the mechanisms driving these 
pathologies, specifically resistance to fibrinolysis (shutdown).40   Further, we hypothesize that both VTE and 
ALI remain significant clinical problems due to a failure to treat this pathology. 
Leading to this hypothesis, we have observed that trauma patients treated with anti-platelet agents prior 
to injury have a reduced incidence of organ failure and improved overall survival.41   Subsequently, Chen et 
al. conducted a retrospective study of 575 trauma patients and showed an independently associated 
decreased  risk  of  acute  respiratory  distress  syndrome  (ARDS)  in  the  cohort  taking  aspirin  prior  to

 
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hospitalization.42    Further, these effects appear to be even more robust when anti-platelet agents, such as 
aspirin, are used in conjunction with a statin.43   On their own, statins have been reported to have protective 
effects following trauma, although no prospective data currently exists.11     In each of these studies, the 
improvement in outcomes has been attributed to the anti-inflammatory effects of these drugs.  However, our 
lab, as well as others, contends that they may be acting through a novel mechanism that acts to reduce 
resistance to fibrinolysis, microvascular and macrovascular thrombosis and their morbid sequelae.10, 44-46 
In an evaluation of nearly 200 critically injured patients, we have identified a spectrum of fibrinolysis.40 
This spectrum consists of three distinct groups (termed phenotypes): normal (or as we termed “physiologic”) 
fibrinolysis, hyper-fibrinolysis and a cohort the exhibits resistance to fibrinolysis (i.e. shutdown).  As would be 
expected, the small cohort of patients exhibiting excessive clot breakdown (hyper-fibrinolysis) had an 
increased mortality attributable to hemorrhage.   Interestingly, nearly 65% of this patient population had 
measured coagulation parameters consistent with fibrinolysis shutdown.   In turn, this group had a higher 
mortality rate attributable to organ failure (Figure 1). 
 
 
Figure 1. Distribution of mortality according to fibrinolytic phenotype. The y axis represents the percentage of 
total mortality per phenotype. The hyperfibrinolytic phenotype had a high frequency of mortality associated with 
hemorrhage. The shutdown phenotype has a high frequency of organ failure-related death. TBI did not reach 
statistical difference between phenotypes but was more common in the shutdown cohort. *p < 0.05. Hyper, 
hyperfibrinolysis; Shutdown, fibrinolysis shutdown; TBI, traumatic brain injury.20 
 
 
Patients with physiologic fibrinolysis ultimately had the best outcomes (Figure 2).  As such, correction of 
the pathologic fibrinolytic state to achieve a physiologic fibrinolysis profile appears to offer a window to a 
therapeutic intervention for coagulopathic patients following severe injury. 
 
 
Figure 2. Survival curves of different 
phenotypes of fibrinolysis. Curve 
demonstrates the time from injury to 
survival 
patterns 
between 
the 
fibrinolysis  phenotypes. The y  axis 
represents  the  percentage  of 
survival, and the x axis represents 
hours from injury. Survival, hours 
after 
injury.20

 
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Furthermore, it is well known that circulating platelets contain multiple granules, with each granule 
containing prothrombotic and antifibrinolytic proteins.31    Recently, we have shown that platelets are potent 
inhibitors of fibrinolysis47, leading to the hypothesis that reduction in platelet activity will abrogate fibrinolysis 
shutdown and ultimately reduce the development of ALI and VTE events.  In fact, the American College of 
Chest Physicians currently advocates for the use of antiplatelet therapy (in the form of aspirin) in orthopedic 
surgery patients at high risk for VTE. 48 
As previously mentioned, the addition of rosuvastatin, an HMG-CoA reductase inhibitor with a number of 
pleiotropic effects,45, 49 has the potential to further reduce resistance to fibrinolysis. Indeed, statins have been 
shown to reduce the circulating level of plasminogen activator inhibitor 1 (PAI-1) in healthy volunteers with 
metabolic syndrome.50   PAI-1 is a protein that prevents tPA from initiating the breakdown of a blood clot and 
is thought to be the primary regulator of tPA in trauma patients.  In vitro studies suggest that statins reduce 
PAI-1 synthesis by blocking transcription (i.e. at the genetic level) in the endothelial cells that line the blood 
vessels.51   In non-trauma patients with septic shock, PAI-1 levels are attributable to endothelial dysfunction 
and are highly predictive of mortality.52    With respect to critically injured patients, we have preliminary data 
showing a nearly 300-fold increase in PAI-1 in this cohort when compared to healthy controls.   Animal 
studies have shown that PAI-1 levels begin to rise several hours following hemorrhagic shock and 
resuscitation53 and can arise from endothelial cells.54 
Although  ARDS  directed  trials  using  statins  (simvastatin  and  rosuvastatin)  55,   56   have  failed  to 
demonstrate a benefit, there are several important differences in the severity of disease between septic 
patients with established ARDS and trauma populations. Moreover, these trials focused on treatment, 
while our objective is directed to prevention. Specifically, the differences between these trials and ours are: 
 
a) Difference in strategies:  in both abovementioned ARDS trials, statins were given as treatment for these 
patients, i.e., when the lung injury was already established, while we are proposing statins as a prevention 
strategy; 
 
b) Differences in populations: there were only 6 trauma patients in the “Rosuvastatin for Sepsis-Associated 
Acute Respiratory Distress Syndrome study” 55, which included mostly patients with pneumonia, a 
complication that occurs in approximately 25% of ICU trauma patients. 2  Similarly, in the HARP-2 trial  56, 
which tested simvastatin to treat ARDS, of the 540 patients only 44 (8%) were victims of trauma. 
 
c) Differences in mechanisms: in the case of statin therapy used to treat sepsis, the hypothesis has been 
that statins inhibit the HMG-CoA reductase thus reducing systemic inflammatory mediators (TNF-α, IL-1ß, IL- 
6, and IL-8). However, statins’ inhibition of HMG-CoA results in a number of pleiotropic effects, as illustrated 
in Figure  3  below.11,  45,  49,  57,  58   Statins  have  been  shown to downregulate endothelial transcription of 
plasminogen  activator  inhibitor-1  (PAI-1),  which  is  massively  up-regulated  post  injury,  resulting  in 
suppressed fibrinolysis, which in turn is associated with macro- and micro-thrombotic complications. 59 
Therefore,  statins’  inhibition  of  PAI-1  in  the  critically-injured  represents  a  promising,  novel  therapeutic 
strategy for the prevention of micro-thrombotic complications such as acute lung injury and ARDS as well as 
macrothrombotic complications as VTE. 
 
 
 
Figure 3: The mechanism of statins: statins inhibit 
the 
conversion 
of 
3-hydroxy-3-methylglutaryl- 
coenzyme A (HMG-CoA) to mevalonate and thus 
prevent cholesterol synthesis. They further prevent 
the downstream production of the isoprenoid 
intermediates and give rise to the pleiotropic effects 
(Note: 
PP=pyrophosphate)58

 
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Regarding the safety profile of statins, the SAILS 55 and HARP-2 trials 56  provided good evidence that 
statins were not associated with higher risk of adverse events among critically ill patients, although there was 
some concern about a potential contribution of rosuvastatin to renal and liver failure. It should be noted, 
however, that both organ dysfunctions are much more common in sepsis patients than in trauma patients. 2 
Incidentally, the SAILS trials required FDA IND regulation because the study sponsor, the manufacturer of 
rosuvastatin, planned on submitting a new indication for the drug (a clear IND requirement). 
Although most of current evidence on statins comes from the cardiovascular field, it has been suggested 
that statins may also have beneficial effects in non-cardiac surgical procedures such as vascular and general 
surgery. 45,  46,  57,  58  Moreover, the beneficial effects of statins were observed in normolipidemic patients, 
suggesting they are independent of lipid lowering effects. 60 Finally, there is some evidence that statins may 
improve recovery from DVT.  In mice with DVT, rosuvastatin and atorvastatin induced significant reductions 
in platelet aggregation, clot stability, thrombus PAI-1, tissue factor, neutrophils, myeloperoxidase, neutrophil 
extracellular traps (NETs), and macrophages, most notably in the earlier DVT stages. 61 In patients with 
DVT, administration of 40 mg/day atorvastatin for three days increased plasma fibrin clot permeability (by 
23%) and lysability (by 15–20%), independent of changes in lipid profile.62 These effects may facilitate 
restoration of the patency of a thrombosed vein. Finally, the JUPITER trial provided convincing evidence that 
rosuvastatin prevented VTE events in healthy, normolipidemic patients, with a very safe profile. 14 
All of the statins currently on the market have similarly excellent safety profiles. 10,  63-65  There is no 
evidence of difference between them. 65, 66 High doses of statin have been associated with some reports of 
bleeding, but current evidence is strong that no risk of bleeding is associated with low dose (as in this study) 
statins. 10 We will be using a low dose of rosuvastatin (20mg) that has been thoroughly validated in the 
cardiovascular surgery literature as a safe and efficacious regimen to improve postsurgical outcomes.  67, 68 
More important, we will be using the only statin (rosuvastatin 20 mg) thus far shown in a RCT to reduce VTE 
incidence in non-hyperlipidemic patients. 14 
Mechanistically, rosuvastatin also seems a logic choice. The following table, Table 1, shows some of the 
mechanisms as well as evidence of VTE reduction in clinical trials and whether or not these statins are 
recommended for cardiac surgery patients. 
 Table 1. 
Anti-thrombotic mechanism 
Clinical 
evidence in VTE 
prophylaxis 
Recommended 
in cardiac 
surgery 
Simvastatin 
 TF expression 
  Thrombin formation 
 PAI-1 
tPA 
 Thrombin formation 
No 
2nd option 
Rosuvastatin 
 TF expression 
Down-regulation of PAI-1 monocytes, 
smooth muscle 
cells and endothelial cells 
 PAI 1 
tPA 
Yes 
1st option 
Atorvastatin 
 Thrombin formation; 
Up-regulates PAI-1 synthesis during 
macrophage differentiation, no effect in 
mature macrophages 
 PAI 1 
tPA 
Thrombomodulin transcription in 
endothelial cells 
No 
1st option 
Pravastatin 
 Thrombin formation 
No effect on PAI-1 
No effect on tPA 
No 
2nd option 
 
 
Rosuvastatin in a low (20mg) dose, based on the above specific effects, its safety profile and being the 
only statin for which there is a RCT demonstrating VTE prevention effects, seems to be a logical choice for

 
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our trial. In addition, it is a first choice in conjunction with aspirin for the postoperative period of cardiac 
surgery. 12 
It is important to note that the dose of aspirin chosen for this trial is in tune with current guidelines. The 
most recent American Heart Association guidelines recommend the use of a higher dose of aspirin based on 
studies that demonstrated that lower doses of aspirin (100–200mg) may be insufficient to effectively inhibit 
platelet function as a result of resistance to the antiplatelet effect of aspirin in the postoperative period 
(“aspirin resistance”), which adversely affected postoperative vein graft patency. 68 
The primary adverse effect of aspirin therapy in any dose regimen is an increased risk of bleeding. 
However, in examining the difference between low-dose (75 - 162mg) and high-dose (>162 - 325mg) 
therapies, a meta-analysis of 22 randomized trials incorporating approximately 75,000 patients found no 
difference in hemorrhage risk between low- and high-dose regimens in all incidences of bleeding (RR 1.62; 
95% CI 1.3 - 2.03) and major bleeding (RR 1.71; 95% CI 1.41 - 2.08). 69 
It is important to emphasize that the comparisons between trauma and cardiac surgery populations 
regarding potential safety of the combination of aspirin and statin is based on solid evidence, as explained 
below. 
 
Comparison between cardiac surgery and trauma patients: Whether the research population (trauma 
patients) is potentially at higher risk from the study medication interventions is relevant to determine FDA 
IND exemption for this trial. Below, we provide a comparison between the population for whom these 
medications are currently recommended (cardiac surgery patients) versus our trauma population. 
We examined several studies to compare the two populations head to head.  Data from the study by 
Berger et al. 70 are summarized below in table 2. 
 
Table 2: Patient characteristics on admission with detail of the diagnostic categories (Berger et al. 55) 
Variable 
Complex cardiac surgery 
Trauma 
Subarachnoid hemorrhage 
Number 
113 
66 
21 
Gender, male/female 
70/43a 
52/14a 
5/16a 
Age, years 
70 ± 10a 
40 ± 19a 
54 ± 9 
Weight, kg 
75 ± 16 
75 ± 13 
68 ± 12 
Body mass index, kg/m2 
26.5 ± 5.0 
24.9 ± 3.9 
24.5 ± 3.4 
SAPS II 
39.3 ± 10.4d 
35.7 ± 15.4d 
33.9 ± 13.6d 
SOFA score at admission 
9.1 ± 1.7a 
7.5 ± 3.1a 
6.3 ± 2.9a 
 
In the above randomized study, compared to trauma patients, cardiac surgery patients were more likely 
to be older, to have a higher BMI, and to have both a higher Simplified Acute Physiologic Score II (SAPS II) 
and Sequential Organ Failure Assessment (SOFA).  In addition, they were much more likely to have prior 
acute renal failure (43% vs.  15%) and to develop acute renal failure (44% vs.  19%) during  hospital 
admission. 
The 2015 study by Zbrozek and Magee 71 also compared these hospitalized populations head to head. 
They observed that, compared to trauma patients, cardiac patients were more likely to require blood 
transfusions (18% vs. 14%), were older and had more comorbidities (as measured by the Charlson 
Comorbidity Index). ICU mortality of cardiac surgery patients was higher than trauma patients, while hospital 
mortality was similar between the two groups. 
Specifically regarding VTEs, trauma patients have an incidence varying from 1.8% to 6.0% depending 
on type of injuries and whether there is systematic surveillance. 72, 73 Mortality associated with VTE can also 
vary depending on the type of VTE but has been estimated to be associated with an adjusted odds ratio of

 
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hospital  mortality of 2.08 (95%CI:  1.15-3.78;p=0.016).72   The most recent guidelines by the   American 
College of Chest Physicians reported the risk of symptomatic VTE among trauma patients to range from 3% 
to 5%.26 Relative contraindications to pharmacologic VTE prophylaxis in trauma include severe head injuries, 
non-operatively  managed  liver  or  spleen  injuries,  renal  failure,  spinal  column  fracture  with  epidural 
hematoma, severe thrombocytopenia, and coagulopathy, all of which would be excluded in our study. 26 After 
exclusion of these high-risk patients, the risk of bleeding in trauma patients receiving VTE prophylaxis has 
been estimated to be at 0.7% (95% CI, 0.2%-1.7%). Comparatively, the same 2012 CHEST systematic 
review 26 estimated cardiac patients to have a VTE risk of  0.5% to 1.1% (thus lower than trauma patients) 
while the risk of bleeding due to VTE prophylaxis for cardiac patients was estimated at 4.7% (range, 3.1%- 
5.9%), which is higher than trauma patients. 
In conclusion, we believe that there is strong evidence that, compared to cardiac surgery patients, 
trauma patients are higher risk of VTE but (assuming appropriate exclusion of the trauma patients at high 
risk defined above) at lower risk of bleeding complications from VTE pharmacological prophylaxis. In light of 
this evidence, we believe there are no reasons to consider the proposed research population at higher risk 
than cardiac surgery patients for whom the proposed medications are considered standard of care. 
In summary, critically injured patients represent a distinct patient population that is at a high risk for 
macro- and micro-thrombotic complications associated with high morbidity and mortality. The current 
pharmacologic therapies used to treat these patients in the intensive care unit are not targeted at reducing 
fibrinolysis shutdown.  Medicating patients at high risk for fibrinolysis shutdown with rosuvastatin and aspirin 
early after injury has the potential to reduce the incidence and severity of post-trauma VTE events. 
 
 
III. Other Preliminary Studies 
 
Fibrinolysis shutdown measurements: Our lab has developed a novel assay to measure fibrinolysis 
shutdown.   74     This assay employs the technique of thrombelastography (TEG), a physical clot-shearing 
method employed to measure the rate that whole blood forms a clot, the strength of the clot, and the rate of 
clot degradation (i.e., fibrinolysis).   The TEG LY30 is the primary parameter used to quantify fibrinolysis. 
However, a limitation to this assay is that it does not measure the magnitude of fibrinolysis shutdown.  When 
patients at risk for organ failure from fibrinolysis shutdown are studied, it is necessary to ensure that they 
have a marked resistance to fibrinolysis, not just a low LY30. 
To address this issue, we sought to modify the traditional TEG assay, adjusting LY30 sensitivity to better 
evaluate the resistance to fibrinolysis.  By adding tPA to whole blood after it has been removed from the 
body, there is an increase in fibrinolytic activity that can be readily measured and quantified by conventional 
thrombelastography. We have previously described this assay as the "tPA-Challenged™ TEG." 59 
We have validated the tPA-Challenged™ TEG in 134 healthy volunteers, resulting in normal distributions 
of fibrinolytic activity using multiple distinct doses of tPA in a dose/response manner.   When the level of 
fibrinolysis in the tPA-Challenged™  TEG of a healthy volunteer is compared to that of bluntly-injured trauma 
patients in the ICU, marked fibrinolysis shutdown is observed in the post-injury patients.  Trauma patients 
with persistent fibrinolysis resistance (i.e. lower than expected fibrinolysis for 5 days post-injury) were found 
to have a trend towards increased VTE; however, our study population was too small to make a definitive 
conclusion based upon these results. 
More recently, we evaluated serial blood samples drawn from trauma patients from the time of injury 
through hospital day 7.  In the first several hours post-injury, patients had diverse levels of fibrinolytic activity. 
By 24 hours post-injury, however, more than 60% showed fibrinolysis resistance greater than the 95th 
percentile of the healthy volunteer population at the highest tested dose of tPA. 
 
 
IV. Research Methods 
 
A.  Outcome Measure(s): 
 
Primary Outcomes: 
     Incidence of VTE 
 
Based on screening duplex ultrasound (US) of legs and central line on day 3.  
Secondary Outcomes: 
     Fibrinolysis phenotypes as measured by traditional and tPA-Challenged™ TEG LY30 
     PAI-1 and tPA levels

 
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     Incidence of ALI within 2 weeks post-injury based on the Berlin Criteria16 
     Ventilator days (as measured by ventilator-free days) 
 
Incidence    of    arterial    thrombotic    complications:    myocardial    infarction    (MI)    and 
cerebrovascular accident (CVA) 
     All-cause 30-day mortality 
     ICU free days 
     Organ failure based off of Denver MOF score75 
 
 
B.  Description of Population to be Enrolled: 
 
The setting of the study is the Denver Health Medical Center, a high volume, level 1 urban trauma 
center.  The patient population to be enrolled consists of all adult trauma patients (ages 18-65 years) 
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 anti-coagulation 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 
 
C.  Study Design and Research Methods 
 
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. 12 
Patients admitted to the SICU will be screened for eligibility in the STAT trial (see above 
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 48 
hours post-injury will be eligible.  If consent is not obtained until 48 hours post-injury subjects will not receive 
the first three blood draws that are to be performed at 6, 12, and 24 hours, respectively.  

 
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Upon consent, blood samples will be obtained at 6, 12, 24, 48, 72, 120 and 168 hours after injury. 
Traditional and tPA-Challenged™ TEG as well as ROTEM Platelet will be performed on these 
samples to evaluate the development of the three fibrinolysis phenotypes. Once the adminstration of 
prophylactic anti-coagulation to the study subject has begun, 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 anti-
coagulation plus the combination experimental drugs (20mg of rosuvastatin and 325mg of aspirin) daily 
either orally or via feeding tube. These doses  are  consistent  with  those  currently  recommended  in  
the  postoperative  period  following  cardiac surgery. {Members, 2011 #61} Patients assigned to the control 
group will receive standard of care anti-coagulation plus identical-looking placebos either orally or via 
feeding tube. Healthcare providers, PRAs and patients will be blinded to study randomization allocation 
(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. 
Trombo Therapeutics, Inc. is not involved in this study. tPA-challenged TEG assay is used for research 
purposes only. The data from this test is not accessible for the clinical care providers and does not affect the 
patient care. We are using this assay to study the clot sensitivity and as a marker for massive blood 
transfusion. The results of tPA-challenged TEG assay will not be used for any clinical decision or research 
subject assignment. At the moment there is no plan to submit tPA-challenged TEG data to the FDA. 
The blood samples will be used to monitor for type of fibrinolysis, function of the biochemical 
mediators of coagulation (see table 3 below) and potential side effects of these medications, as 
explained in more detail below. 
 
 
Table 3: Biochemical Mediators of Coagulation and Fibrinolysis 
Coagulation Factors 
Fibrinolysis Factors 
PAI-1 
Plasmin/Antiplasmin Complex (PAP) 
tPA 
TAFI 
D-dimer 
α2 macroglobulin 
Thrombin/Anti-thrombin complex (TaT) 
α2 anti-plasmin 
Free Anti-thrombin 
C1 esterase 
Factor VII 
Angiostatin 
Protein C 
α-enolase 
Protein S 
Polyphosphates 
Platelet aggregation 
Myosin 
Functional fibrinogen 
Histones 
 
 
Multiple methods of laboratorial analysis will be employed to evaluate these parameters.  The methods 
and techniques include:   the aforementioned TEG analyses to evaluate the mechanical properties of the 
blood clots; ROTEM aggregometry to assess platelet function; enzyme-linked immunosorbent assays and 
quantitative proteomics to compare and contrast coagulation protein levels during statin and aspirin 
treatment; and quantitative mass-spectrometry metabolomics to investigate the links between  the  metabolic  
derangements  that  occur  during  trauma  and  shock  with  the  function  of  the coagulation proteins 
(specific focus on the development of fibrinolysis phenotypes).  Ultimately, sampling at each time-point will 
require approximately 21 ml of blood to perform the necessary assays (please, see table 4 below with the 
volume of blood required to perform the coagulation assays).  Two additional samples may be 
collected for safety monitoring after consent is obtained and after the third dose of the 
study drug. To reduce redundancy, safety labs will not be collected if there has been a 
result within the past 12 hours. Over the course of the study, a maximum of 9 blood samples will be 
obtained with a maximum total of approximately 163 ml of blood drawn. 

 
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Study medications or placebo will be administered during hospital stay 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. 
A lower extremity ultrasonography will be conducted on the third day the patient receives the study drug. 
If the subject is discharged sooner than the third day the patient receives the study drug, lower extremity 
ultrasonography will not be done.  The test will be used to evaluate the central line sites and veins in the legs 
for blood clots.  The results of the ultrasound test will not be available for patient clinical care as routine 
ultrasound surveillance for thrombotic events as this is not recommended for trauma patients according to the 
latest guidelines. 84  
We will monitor function/damage of liver, renal and muscle before initiation of therapy (if the patient 
already has a recent test of these functions within 12 hours of enrollment, the result of these tests 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 consective 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, we will use the accepted definition of 3 times the baseline of the AST test 
as the criterion for interruption of therapy; 
3.  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 

 
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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   We will define AKI as serum creatinine increase greater 
than 2x of baseline (>Grade 1, based on AKIN criteria) as the criterion to interrupt therapy. 
4.   Muscle injury:  Myositis and rhabdomyolysis are rare sequela 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    We will use this threshold to clinically quantify myositis, 
preceding potential development of rhabdomyolysis, as well as the criterion to interrupt therapy. 
5.  If the study patient receives aspirin, as prescribed by their SICU attending, administration of the study 
drug will be stopped. 
6. 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  a  SAE  and  will  trigger  an 
immediate review by the DSMB. 
 
Data collection/storage/maintenance: Trained PRAs will collect demographic, clinical, laboratory and 
outcome data, coordinate collection of blood samples with appropriate hospital personnel and perform 
laboratorial analyses.    Data will be archived using Microsoft Excel.  Samples will be stored for future 
research in our Sample Bank (if permission is obtained from the patient or the LAR).  PRAs will use the 
patient’s medical record for data collection.  Data from medical records will be collected while the patient is 
being given the study intervention, or up to 30 days post-injury whichever is longer.  If the study intervention is 
discontinued before 30 days, data collection will still continue to evaluate 30 day mortality.  
 
  
  
  
  
Diagram of STAT study design 
  
  
  
  
  
  
  
 
 
 
Eligible trauma patient (adult, admission to SICU, 
anticipated hospital stay≥3 days, no exclusions) 
 
 
 
  
  
↓ 
  
  
Consent for study 
  
  
↓ 
  
  
Blood sampling starts 
  
  
↓ 
  
  
 
 
 
Pharmacological prophylaxis of VTE starts per SICU 
protocol 
 
 
 
  
  
↓ 
  
  
DHMC pharmacy randomizes the patient 
  
  
↙ 
↘ 
  
  
 
Rosuvastatin 
+ Aspirin 
 
Placebo  
 
 
  
  
↓ 
↓ 
  
  
  
  
  
Blood sampling continues. Doppler US of IV/central 
line sites and legs on day 3 
  
  
  
  
 
 
 

 
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D.  Description, Risks and Justification of Procedures and Data Collection Tools: 
 
     Initial screening: 
 
History,  physical  exam  and  clinical  data  (laboratory  and  radiographic  reports)  obtained 
during the patient's trauma work-up and stabilization will be reviewed for enrollment eligibility 
 
These data will not subject the patient to any additional study-related risk, as no study 
intervention will take place 
 
     Blood collection/phlebotomy: 
 
Standard hypodermic venipuncture will be employed to obtain blood samples for evaluation 
only if no IV access already exists. Trained hospital personnel will draw blood samples.  
 
Approximately 21.5cc per collection (~150.5cc total over 7 days) will be required for analysis 
 
Risks are minimal and include pain, bruising, bleeding, infection and damage to surrounding 
structures 
 
These procedures are necessary to conduct laboratory analyses and its results will not 
interfere with patient care 
 
     Medications: 
 
Aspirin:  aspirin  is  a  non-steroidal  anti-inflammatory  drug  that  blocks  the  chemical 
messengers  responsible  for  platelet  activation;  pertinent  side-effects  of  aspirin  are 
uncommon and include systemic bleeding, gastrointestinal bleeding and allergic reaction 
(see above for risks) 
 
Rosuvastatin: statins are HMG-CoA reductase inhibitors that have been shown to have 
multiple effects beyond cholesterol-synthesis regulation; pertinent risks of statin therapies 
are rare and include liver and kidney dysfunction, and myopathy (see above for risks) 
 
Both  aspirin  and  rosuvastatin  are  FDA  approved  medications  and  standard  of  care  in 
populations at lower risk for adverse events than the proposed trauma population 
 
As there is no current clinical treatment for fibrinolysis shutdown, a sequelae of trauma with 
both high morbidity and mortality, the proposed treatment strategy has acceptable risks that 
do outweigh the potential risks of treatment 
 
     Lower extremity ultrasonography: 
 
This is a non-invasive radiographic test that uses external sound waves to produce images 
of internal anatomic structures 
 
This test will be used to evaluate the central line sites and veins in the legs for blood clots 
 
The risks of ultrasonography are minimal 
 
This procedure is necessary to survey for and/or diagnose DVT ·        
 
The results of research ultrasound test will not be available for patient clinical care as routine 
ultrasound surveillance for thrombotic events is not recommended for trauma patients 
according to latest guidelines due to high number of false positives. 84 
 
Ultrasound screening images will be stored in a secure location on Denver Health server and 
interpreted by an independent radiology specialist prior to interim analyses.     
 
 
 
E.  Potential Scientific Problems: 
 
There are some potential problems with the significant variation in the current use of aspirin, which some 
surgeons use for VTE prophylaxis in trauma patients while others do not. As this is a pragmatic trial, the 
investigators will not interfere with the clinically indicated use of aspirin.  If the study patient receives aspirin, 
as prescribed by their SICU attending, the patient will be withdrawn from the study and all blood draws will 
stop. The DHMC pharmacy will be aware of the group assignment; therefore, if the patient is placed on 
aspirin per his/her attending’s prescription, no additional dose of aspirin will be given. If the patient is 
assigned to the experimental group, there is no contamination;  however,  if  the  patient  is  assigned  to  the  
control  group,  there  is  the  potential  for contamination of the study. We will adjust for this in the as–treated 
analysis (see below). 
 
 
 
 

 
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F.  Data Analysis Plan: 
 
Our sample size is defined and limited by our trauma center volume. Based on the analysis of our 
screening data in the past 16 months of study enrollment our annual SICU trauma admission volume was 
about 700 patients. The exclusion rate was over 90% in addition to 60% refusal rate. We were able to enroll 
roughly 1/3 of what we expected originally. This Phase II study may be underpowered to detect VTE 
reduction, depending on the observed incidence among patients with fibrinolysis shutdown. Trauma ICU 
series have reported variable VTE incidence under surveillance from 3-6%, in which case we could only 
detect reductions to 0-1% with 80% power, 95% confidence, and 2 equally spaced interim looks at the data. 
However, certain at-risk patients (possibly including shutdown patients) have higher VTE rates of 11-28%, in 
which case, the study could detect 39-64% relative reductions. Thus, we designed STAT as adaptive with 
pre-planned reassessment of sample size to detect a meaningful >50% relative reduction in VTE, 
in/exclusions, and other parameters during blinded interim analyses. 
 
During the blinded interim analyses, the DSMB will reassess: 
o 
Sample size, with a target to reach >50% relative reduction in VTE 
o 
Inclusion and exclusion criteria 
o 
Recruitment procedures 
o 
Additional adverse events 
o 
Addition of secondary outcomes 
o 
Expansion to a multi-center trial 
The analysis will contrast the outcome of the patients randomized to statin and aspirin therapy versus 
those randomized to placebo. In addition, we will test an interaction between group allocation and the 
presence of fibrinolysis shutdown on the development of thrombotic complications.   All analyses will be 
conducted as intent-to-treat initially and as-treated subsequently. Primary and secondary outcomes as well 
as adverse events will be compared between groups. Subgroup analyses by VTE risk measured by the 
Greenfield score 83 are planned. 
Continuous variables (i.e. PAI-1, LY30, ventilator free days, and intensive care unit free days) will be 
contrasted using a non-parametric test.   Survival analysis will be performed using  Cox  proportional 
regression and Kaplan-Meier curves.   Dichotomous outcomes (mortality, adverse events, thromboembolic 
events) will be contrasted between treatment arms with a chi-squared test or Fisher Exact test if expected 
cell values are <5.  
 
We request permission to conduct the first interim analysis to be performed at the enrollment of 40 
patients. In this adaptive trial, changes in sample size requirements were to be assessed at each interim 
analysis. The first interim analysis was originally planned upon enrollment of 147 subjects (two interim and 
one final analyses were planned to be performed in equally spaced intervals). However, due to unexpected 
slow enrollment (different than assumed during sample size calculations, see details above) it seems prudent 
to anticipate it in order to re-assess sample size requirements. The results of this interim analysis will allow us 
to re-assess our assumptions for a more precise sample size calculation for continuation of the trial.  
 
If adjustment for confounders is necessary, Poisson regression with robust standard errors will be used 
for dichotomous outcomes and mixed models for continuous outcomes with appropriate transformations to 
approximate normality as needed. 
Missing data will be minimized by careful, onsite, concomitant data collection through 24/7 coverage by 
our PRAs. For variables with more than 10% missing data, we will conduct missing data diagnosis (MAR, 
MNAR, MCAR), and if pertinent, missing data treatment with MICE. 
 
Data  Safety  Monitoring  Board:  All  analyses  will  be  monitored  by  an  independent  Data  Safety 
Monitoring Board (DSMB).   All serious adverse events (SAE) and protocol violations (UAP) will be 
communicated to the DSMB. The DSMB will convene every 12 months for the 5 years of the study or more 
often if there are concerns about SAE or UAP as determined by the DSMB Chair. Each meeting will be 
approximately 1 ½ to 2 hours in duration and attended in-person or via conference call. We expect that each 
meeting will require a maximum of 2-hour preparation time (to read and review pertinent materials). The 
Chair of the DSMB may call ad hoc meetings as needed should unexpected or adverse events be identified 
and require review. These ad hoc reviews will consist of short conference calls or exchange of email. The 
first meeting will convene before enrollment starts.  If necessary, the DSMB can require amendments to be 
submitted to the IRB to ensure safety of the subjects.  Confirmed members of the DSMB are as follows: 
 
 

 
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o M. Margaret Knudson, MD (chair) 
 Professor of Surgery 
 University of California, San Francisco 
 Division of General Surgery 
 Medical Director for the Military Health System (MHS) Strategic-ACS Partnership 
o Alden Harken, MD 
 Professor of Cardiothoracic Surgery 
 University of California, San Francisco 
 Chief, UCSF-East Bay Surgery Program 
 Chair, Department of Surgery, Alameda County Medical Center 
 Division of UCSF-East Bay Surgery 
o Sung-Joon Min, PhD 
 Associate Professor of Healthcare Policy and Research 
 University of Colorado AMC 
o Michael Wang, MD 
 Associate Professor of Pediatrics-Hematology/Oncology 
 Clinical Director, Hemophilia and Thrombosis Center 
 University of Colorado AMC 
 
 
G.  Summarize Knowledge to be gained: 
 
On the basis of this randomized, controlled Phase II study, we hope to better understand the following: 
 
 
the efficacy of aspirin and rosuvastatin in the reduction of the incidence of VTE in critically 
injured trauma patients at risk for these complications 
 
the mechanisms involved in the coagulation and inflammatory cascades linking fibrinolysis to 
VTE and other thrombotic complications by examining the effect of aspirin and statin therapy on 
PAI-1, tPA levels and fibrinolysis phenotypes 
 
The results of this Phase II study will assist in determining the efficacy and safety of combination statin 
and aspirin therapy in severely-injured patients, will assist in determining the pathway through which trauma- 
induced coagulopathy determines late post-injury thrombotic complications and will enable the design of a 
multicenter, randomized, controlled study adequately powered to determine the level of reduction in the 
incidence of VTE in this population. Furthermore, we will develop a systematic algorithm to treat the diverse 
fibrinolysis phenotypes. In sum, this and future studies will help broaden our understanding of the complex 
mechanisms that underlie trauma-induced coagulopathy. 
 
 
H. References: 
 
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