Trying Hard - Trials in EM Research

The Gist:  If one follows EM blogs, podcasts, or tweets for any period of time, it's immediately apparent that application of evidenced based medicine is the expectation.  Within the EM context, however, research and evidence face incredible challenges, partially due to the improvisational, desperate nature of the job.  Global discourse over TXA in trauma and epinephrine in cardiac arrest highlight learning points regarding the complexity EM research.  Note: This was part of a behemoth post, so this is Part 2 (Part 1 takes a gander at the CRASH-2 trial and under-utilization of TXA in the context of study design/result interpretation).


The papers behind many of these musings:  Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. and Prehospital Epinephrine Use and Survival Among Patients With Out-of-Hospital Cardiac Arrest.  

• On the PHARM Podcast, Episode 12, when Dr. Minh Le Cong and Tim Noonan highlighted some problems with trials in EM with medications like epi and they do a great job reviewing some of the issues below.  

What makes evidence based medicine different in EM?

Diversity of the Population - ED patients often have trauma or an undifferentiated illness/complaint that causes them to present to the ED.  Trauma, naturally, is not uniform and certainly not predictable in terms of enrolling patients. 

• Mechanism of action -  There are seemingly infinite ways in which people manage to harm themselves or others.  Every study that investigates trauma will have some degree of variation (heterogeneity) in penetrating and blunt trauma, burns, etc.  Thus, inclusion criteria may rely on a clinician's judgment or an objective systemic endpoint (BP, HR, etc).
• Predictability - Within a population, estimates exist regarding the incidence/prevalance of the disease.  One of the beauties of EM is never knowing what type of patient is going to roll through the doors next.  Sometimes we can guess (or hope), but that's about the extent.

Cost - In EM, many therapies are relatively inexpensive:  chilled saline, epinephrine (epi) , and TXA are all fairly cheap.

• Pharmaceutical companies are not inclined to sink significant funds into examining the efficacy of these therapies.  In stark contrast, some therapies like activated protein C (Xigris, drotrecogin alfa) seems to get a great deal of journal/media attention for an intervention with limited clinical utility and no proven benefit.  Activated protein C,  far more expensive than drugs such as TXA/epi, has a clear pharmaceutical backing drawing more research and publicity.

Vulnerability of the Population  - The day a patient requires emergency care is often the worse day of their life.  

• Oftentimes, one is unable to obtained informed consent for study participation due to the nature of a patient's injuries, mental status, or the critical nature of events.   The final rule on Exception From Informed Consent (EFIC) in the U.S. waived the need for informed consent in EM research in 1996. Note:  The Nov 2005 volume of Acad Emergency Medicine details this topic thoroughly.  Although in emergent situations, informed consent may be waived legally, IRBs often have issue with approving these studies.  This rule does not apply internationally.  For example, the authors of CRASH-2 reported that some of the delay in TXA/placebo administration existed in the delay in obtaining informed consent.  
• The population is comprised of pregnant women and children, two groups that experimenters are already reticent to include in trials. 

Unique Environment - A certain MacGyver-esque quality exists in EM where there's some agreement that nearly anything (reasonable) may be done in order to save a life.  Due to the oft undifferentiated and improvisational nature of the trade, it's much more difficult to go through many of the standard research protocols.   

• Time proves critical in many EM situations.  Thus, a physician's impression of a situation (or gestalt) may be the only thing guiding critical care, as some diagnostic queries may take too long.  This is especially notable in the time frame that TXA works best (within 3 hours of trauma, but <1 hour is superior).  
• Along these lines, a fraction of EM practice incorporates salvage therapy.  Individuals may have a lower threshold for utilizing a treatment due to the notion that the intervention is a "last-ditch effort."  The use of epinephrine in cardiac arrest is an example in which many people have questioned, "what can be the harm if the patient is already dead?"  Unfortunately, epinephrine's primary benefit seems to be in establishing ROSC so the patient's family (and the patient's body) then bears the burden of an alive patient with little to no neurological recovery.  Certainly some patient's fall into the area where they can have both ROSC and retained neurological function (therapeutic hypothermia!); however, the studies don't look promising that this is positive at the population level.  It's extremely difficult to refrain from doing something.  
• The population is (generally) very sick.  Many cohorts have confounders or confusing secondary endpoints where survivor bias plays a significant role.  TXA's failure to significantly reduce blood transfusions in CRASH-2 may serve as an example of this.
• Much of EM is protocol driven, particularly in the pre-hospital realm.  Thus, study design may need implementation/approval at the system level.  The initial study in Houston, TX regarding permissive hypotension in the penetrating trauma patient is an example of a successful study with a protocol based intervention. 

Standard of Care - The current dialogue regarding epi in cardiac arrest serves as an excellent example of how a standard of care, widely accepted prior to rigorous studies and modern research design, requires one to assume the burden of disproof.

• Placebo controlled trials may be difficult to get past an IRB with something that has become a "standard of care," even if the "standard of care" has never been adequately investigated.  

This paper, by Dr. Tim Coats in the the BMJ, discusses the challenges of conventional research in the EM realm and advocates for emphasis on pragmatic trials over explanatory trials in EM.  It really is helpful.

Size Matters? - Tranexamic Acid in Trauma

The Gist: There's a good bit of chatter in the EM world focused on picking apart literature and trials to ensure that decisions and clinical treatment are up to date and evidence based.  This is amazing and something many neglect as they merely peruse a paper's abstract.  Might there be a time, however, when one should let some study design technicalities slide?  I'm certainly not an expert on this subject, but a few recent debates on tranexamic acid (TXA) and epinephrine (epi) piqued my interest in this subject. Note: This was a behemoth post, so I've split it in two because my attention span is not nearly that long.

Recently, I heard an impromptu debate from a grand rounds lecture on the CRASH 2 study regarding TXA in trauma patients.  The trial wasn't well received by the audience because of design issues.  I recalled attempting to sell my surgery attending on the idea after I listened to the EMCrit podcast on TXA...he was totally unaware of the drug.  This served as a impetus to review research/evidence problems specific to EM - an issue on my mind since the Japanese epi studies were published earlier this year, generating controversy regarding ROSC and neurological outcomes.    

The paper:  The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial

What did this RCT show?  Dr. Andy Neill of Emergency Medicine Ireland reviews and interprets the study here and the NNT review of TXA is also excellent. Basic rundown:

• Reduction in all cause mortality (RR 0.91, CI  0.85–0.97, p=0.0035) when tranexamic acid was given to trauma patients who were bleeding or at risk for bleeding (2)
• Reduction in the risk of bleeding death (RR 0.85, CI 0.76-0.96, p=0.0077)  best benefit in patients who received it within 1 hour of injury (RR 0.68, p<0.0001) (2)
• Subgroup analysis planned a-priori

Ok, now onto some criticisms of the CRASH2 study:

• Size - Some argue that the large scale of the study (n=20211 patients in 40 countries at 274 hospitals) weakened the study results.  Size seems to be one of the commonest reasons that a study is cited as weak.  In EM, some studies have small numbers because of the infrequency of some presentations (toxic ingestion, difficult airways, etc).  These studies are criticized for their lack of generalizability in other populations.  CRASH-2, however, received some criticism because the argument that the size created heterogeneity in the population.  Instead of believing that this might increase the generalizability across the globe, some believe that the size creates protocol standardization failure, meaning the results aren't actually applicable.  Also, it is true that large studies can achieve power more easily than smaller studies, perhaps leading to detection of small clinical benefits. 
• Effect - Absolute reduction in bleeding death observed in the treatment group is only 0.8%, so the number needed to treat (NNT) is 125 versus a NNT of 67 in those who received TXA earlier in their course.  Thus, although statistically significant, the potential clinical benefit for an individual patient is small.  Furthermore, some of the endpoints such as transfusions, were not decreased by TXA.  
• Protocol - Patients were entered into the study based on physician's determination that they are "reasonably certain anti-fibrinolytic agents are indicated."  This creates a subjective entry point rather than a quantitative, objective point.  
• Time - The evidence strongly demonstrates that effect size depends on the time of administration.  Harm may exist in administration of TXA after 3 hours.  Due to transport time, some doubt their ability to meet this time frame. 

So, then, why become a fan of TXA in the bleeding trauma patient?

• TXA is extremely cheap for an intervention that may save lives.  The U.S. Department of Defense formulary cost is $39.12 per 10 mL vial containing 1 g of TXA ($80 for the regimen used in the trial). The cost at CVS Pharmacy is $101.99 per 10 mL vial containing 1 g of TXA ($204 for the regimen used in the trial) (1).  The drug also demonstrated cost-effectiveness in country-based analysis of the CRASH-2. 
• With regard to the size of the trial, this study would suggest that the the benefits of TXA have the potential to be generalized worldwide (as the cohort was rather international), a quality that many studies lack.
• In addition to the subjective entry point of a patient being at risk for significant hemorrhage, there was some objective criteria to guide clinicians. Ex: the patient had to have significant hemorrhage (systolic blood pressure less than 90 mmHg and/or heart rate more than 110 beats per minute), or meet the clinician's gestalt of being at risk of significant hemorrhage within 8 hours of the inciting event.
• The side effect profile was remarkably good, especially in the group that TXA is really indicated for (early post-event, within 3 hours).  Compared with pharmaceuticals like Factor VII, which is markedly expensive, there is a paucity of thrombotic events associated with TXA.  Also, blood product transfusions are not benign.  Early utilization of this drug is likely far less expensive and harmful than massive tranfusions that often ensue.
• The patients that are likely to qualify for TXA are incredibly ill.  The reduction in  mortality by absolute numbers may be modest, but this cohort doesn't generally do well regardless.  In an era when many other standard interventions have questionable efficacy (epinephrine in cardiac arrest, PPIs in UGIB, etc) rejection of the benefits of TXA seems in-congruent.
• The time frame issue seems work-able, especially if TXA were implemented in the pre-hospital setting.  
• The findings of CRASH2 have been demonstrated outside of this large trial.  The MATTERs study, a retrospective analysis of 293 patients who received TXA in the US and UK military combat setting in Afghanistan demonstrated a statistically significant mortality benefit in patients who received TXA compared with those who did not (17.4% vs 23.9%).  The patients that received TXA were sicker than those who didn't (mean Injury Severity Score, 25.2 vs 22.5, P .001) (4). 

References:

1.  Tranexamic Acid for the Trauma Patient: A Critical Review of The Literature

2.  The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial

3.  Tranexamic Acid for Trauma
4.  Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study.