Thanks, Corinne, for the introduction, and thank you all for having me. I'm delighted to be here speaking, especially this late in the day on a Tuesday, the last day of Congress. But like Corinne said, my name is Melanie Smith-Kendenny. I am a surgery, trauma, and burn ICU clinical pharmacy specialist at the Medical University of South Carolina. I have no disclosures related to today's presentation. And we are going to be reviewing the newest pharmacologic strategies in trauma today. So we're going to start off with an audience participation question. In an adult trauma patient, not on anticoagulation, who requires massive transfusion, do you routinely utilize procoagulants in addition to blood transfusion? And if so, what agents? So we'll just start with hands for A, no procoagulants, looks like the majority of people, B, factor VII, C, three-factor prothrombin complex concentrate, D, four-factor or K-centra most of the time, and activated four-factor prothrombin. Okay, it looks like most people don't use procoagulants. And that's good, because we're going to talk about the procoag randomized controlled trial. This looked at the efficacy and safety of the early administration of four-factor prothrombin complex concentrate in patients with trauma at risk of massive transfusion. So historically, there have been some observational studies that have looked at the use of four-factor PCC in patients who were requiring massive transfusion to help with that thrombin burst and increasing, boosting that thrombin burst to decrease overall blood product consumption. But that came along with the risk of the adverse event of thrombosis. So there have been a couple of newer studies that have looked at this, and they found that adding four-factor PCC to FFP in patients who were receiving massive transfusion did decrease the overall use of blood products in addition to decreasing mortality without that risk of thrombosis. So this study was a randomized controlled trial that wanted to assess if the addition of four-factor PCC to a balanced resuscitation was superior to transfusion alone in patients at risk for massive transfusion for the use of 24-hour blood product consumption. So this study was conducted at 12 level one trauma centers in France. It included adults with trauma at risk for massive transfusion. And they defined that as patients who required at least one unit of packed red blood cells while pre-hospital or within an hour of admission to the emergency room, and that they had an assessment of blood consumption score of at least two. That ABC score ranges from zero to four, and it gives patients points for things like hemodynamic instability, a positive FAST exam, or a penetrating mechanism of trauma. So this study included mostly males. They had a median age of 39 years, and they had a median injury severity score of 36. So an ISS is something that's used mostly in research to define the severity of injuries. It looks at the trauma to each body system and gives each of those a score. The scale is zero to 75, and so anything greater than 15 is considered major polytrauma. So this 36 indicates that these patients were severely injured. They excluded patients who had traumatic cardiac arrest, devastating injuries, or pretreatment with any anticoagulants. They randomized 327 patients with 164 of them receiving 25 units per kilogram of four-factor PCC and 160 to the placebo arm. All of the patients received the same resuscitation management. So that was a balanced transfusion ratio of PRBCs to FFP of 1.1 to 1.2. They could receive TXA at the discretion of the site, and they received cryoprecipitate for a fibrinogen of less than 1.5, platelets to maintain a level greater than 50, and viscoelastic monitoring after they were enrolled in the study. The primary outcome included total blood product use with PRBCs, FFP, or platelets consumed in the first 24 hours. We'll talk about some of the demographics here. So most of the patients had a blunt mechanism of injury. Most of them required some sort of operative procedure for hemostasis management, and they all had an assessment of blood consumption score of 2. Their prothrombin time ratio was all greater than 1.2, so a level of greater than 1.2 indicates that a patient does have coagulopathy from trauma. The majority of them did receive massive transfusion for meeting either one of these criteria, either the transfusion of greater than or equal to 3 units in the first hour or more than 10 units in the first 24 hours. The only difference in baseline characteristics were looking at the use of tranexamic acid where you had more of that administered to the patients in the placebo arm, and then the dose of fibrinogen concentrate was higher in the four-factor PCC arm. When you look at the efficacy, there was no difference in the median 24-hour blood consumption use at 12 units for PCC versus 11 units for placebo with an absolute difference of 0.2 units. For the secondary outcomes, they found no difference in mortality, time to hemostasis, or individual blood component use. However, when you looked at safety, we did see some divergence in results. So there was a significantly increased risk of thromboembolic events in the four-factor PCC group with an absolute difference of 11% and a relative risk of 1.48. So some strengths of this study. This patient population was indicative of a true risk of mass transfusion. They had a high injury severity score, a high calculated ABC score, and a high rate of pre-hospital hypertension. So this was a sicker patient population than what was seen in some of the previous literature. So I think that was a really good strength of the study. Some weaknesses included that it was isolated to only a French patient population, so I'm not sure how applicable that is in other countries. One of the biggest weaknesses was that viscoelastic testing was not used until after study enrollment. The problem with this is that if you're using the viscoelastic testing after you've already enrolled the patient, we may be administering PCC to patients who aren't truly coagulopathic, and that may increase the risk for VTE if we're giving PCC to patients who don't need it. Additionally, the risk for massive transfusion does not equal an actual need for massive transfusion. So again, you're risking that you may be giving these patients PCC when they wouldn't have needed mass transfusion to begin with, so you're increasing your odds that those patients would develop a VTE. So overall, this trial found no clinical benefit to adding four-factor PCC in patients at risk for mass transfusion and possible harm from thromboembolic events. So all of you that raised your hands that said you are not administering PCC, I would say continue to not do that. Okay, now we're going to shift away from procoagulants to anticoagulants and looking at the prevention of venous thromboembolism. So this study was the aspirin or low-molecular-weight heparin for thromboprophylaxis after a fracture. Historically, guidelines have recommended that we use low-molecular-weight heparin to decrease the risk of venous thromboembolism in patients with orthopedic trauma, but there have been some newer studies that have looked at using aspirin as an alternative regimen in this patient population, but there have not been any head-to-head studies to this point. And the reason why aspirin may be preferable is there are studies looking at patient preference for oral thromboprophylaxis, and they have shown that patients strongly prefer an oral regimen after orthopedic injuries. So this randomized controlled trial was designed to assess if aspirin was non-inferior to low-molecular-weight heparin for the prevention of thromboembolism in patients with orthopedic trauma. So our next audience participation question. What pharmacologic thromboprophylaxis do you use at your institution for isolated orthopedic trauma, assuming a patient has normal renal function? So hands for A, low-molecular-weight heparin, looks like most people. B, unfractionated heparin, C, aspirin, and you see a couple hands for aspirin back there. Direct oral anticoagulants, and E, any other combination of agents. So it looks like most people are using low-molecular-weight heparin. This study was done at 21 trauma centers in the United States and Canada, and it included adults with either an operative extremity fracture or non-operative or operative pelvic or acetabulum fractures. It was composed primarily of men with a median age of 46 or 44 years and a median injury severity score of 9. So if you remember what we talked about with the PROCOAG trial, that ISS of 9 is less than 15, so these weren't major trauma patients. Their mean hospital duration was 5.3 days. They excluded patients who presented late after their injury. They excluded patients who were on any pre-enrollment anticoagulation or any patient that had a medical history that would predispose them to a higher risk of venous thromboembolism. They enrolled 12,000 patients, which is pretty impressive, and they had a very high rate of follow-up data. The groups included low-molecular-weight heparin dosed at 30 milligrams BID. It was allowed to be adjusted for obesity, augmented renal function, or renal dysfunction, or anything else according to the site protocol. And they compared that to patients who received aspirin 81 milligrams twice daily. The reason that they chose the twice-daily dosing was just to lower your risk that you're going to have more adherence to once-daily aspirin compared to the BID, low-molecular-weight heparin. Their per-protocol analysis said that patients had to receive 80 percent of their assigned in-hospital doses. They were allowed to continue post-discharge prophylaxis as long as they remained on their same treatment arm, and that was per, the duration was per site protocol. But both arms did have an average of 21 days of post-discharge prophylaxis. And then their primary outcome was death at any cause at 90 days. So for that primary outcome, they did find that aspirin was non-inferior, but not superior to low-molecular-weight heparin, although if you look at your numbers there, there's a very small difference between the two. Secondary outcomes, which were also assessed at 90 days, they found more DVT in the aspirin group compared to low-molecular-weight heparin, with 2.5 percent in aspirin and 1.71 percent in the low-molecular-weight heparin, with a risk difference of 0.8. They did find no difference in pulmonary embolism-related death or non-fatal PE, and then no difference in any of the other secondary outcomes, including bleeding, wound complications, or surgical site infections. So the bottom line. Some of the strengths of this study included that they evaluated an alternative oral thromboprophylaxis treatment that may have strong patient preference. They had a very high rate of follow-up and adherence rate with a large number of patients. Weaknesses, we all know that the long half-life of aspirin precludes needing to use it twice daily, so this isn't necessarily needed clinically and not real-world practice. Additionally, that long aspirin half-life may have provided an increased thromboembolism protection at discharge in that patient population. And then, as we talked about earlier, that median ISS with isolated orthopedic trauma kind of limits our applicability to most critically ill patients. And finally, our contemporary guidelines recommend higher enoxapirin dosing in trauma, with most guidelines recommending starting off at at least 40 milligrams BID and adjusting for obesity, renal function, things like that. So these patients may have been underdosed on the low-molecular-weight heparin, which may have increased their risk for VTE. So these findings support the use of aspirin thromboprophylaxis for isolated orthopedic trauma if you are okay with that slight increased risk of DVT, but its use in the critically ill polytrauma patient needs further evaluation. So in conclusion, I would not recommend four-factor PCC for mass transfusion patients based on the results of the PROCOAG trial. For aspirin for isolated orthopedic injuries and thromboprophylaxis, this could be considered if you have a patient who is very adverse to a parenteral form of thromboprophylaxis, but I would not recommend it for your critically ill polytrauma patient. All right. Thank you, guys.

trauma care

PROCOAG trial

prothrombin complex concentrate

thromboprophylaxis

orthopedic trauma