1. Tranexamic acid: A PICO Review
Holly Gagne
COHP 450
Ferris State University
This PPT is a review on a PICO question about tranexamic acid for the College of Health Professions class 450 at Ferris State University presented by Holly Gagne

2. INTRODUCTION
Tranexamic acid (TXA) is an antifibrolynic to prevent blood loss
Two types of administration:
IV: 1 dose preoperatively, 1 dose intraoperatively
Intra-articular/topically
Derived PICO question:
In patients undergoing a total knee arthroplasty, does the use of tranexamic acid intra-articularly versus receiving the standard divided dose of intravenous tranexamic acid reduce bleeding more effectively?
The purpose of the presentation is to discuss the PICO question and research information about its validity.  
Currently in many orthopedic surgeries an antifibrolynic drug, tranexamic acid is used to help control blood loss. It is especially common in total joint arthroplasties since there can be a large amount of blood loss.  
Studies have shown that the addition of TXA can decrease EBL in a TKA by a mean of 500 ml and reducing the need for a blood transfusion by 45%. 
There are, however, different approaches to the surgery itself as well as the use of this drug. Standard intravenous doses are divided into two doses: 
1 dose preop about 20 minutes prior to the inflation of the tourniquet and a second dose approximately 15 min before tourniquet deflation. Sometimes a third dose is given about 3 hours after the intraoperative dose. 
Another method is to use the medication topically or intrarticular during the procedure. Diluted with NS, it is applied directly with the joint for a minimum of 5 min prior to deflation of the tourniquet.  
With the differences in these approaches the following PICO question was derived: 
In patients undergoing a total knee arthroplasty, does the use of tranexamic acid intraarticularly versus receiving the standard divided dose of intravenous tranexamic acid reduce bleeding more effectively?

3. Literature Search Search Engines: Keywords: Results:
FLITE library online
Pubmed
Keywords:
TKA, tranxaemic acid, intravenous, topical intra-articular, surgery, clinical trial, blood loss
Results:
Varied but successful
Many orthopedic and surgical journals
Pub Med through the FLITE library search engine was the search engine utilized. It allows for advanced searches with multiple keywords. It also allows for search criteria to change the article years to less than five years old and to search for documents with full text. Another key feature is once a specific article is selected, similar articles are then filtered the side. 
Multiple searches were done because keywords did not always pick documents that were appropriate. For example searching total knee arthroplasty did not pick up as many articles as the abbreviation TKA. Key search words included: TKA, TXA, topical, intraarticular, intravenous, surgery, clinical trial, and blood loss 
As mentioned previously, multiple searches were compiled to find peer-reviewed articles that were appropriate for this research. Many articles contained information on TXA but not necessarily for a TKA or were a comparative study. TXA can be utilized for other conditions or surgeries to minimize blood loss and accounted for many search results. The most pertinent searches brought up articles from journals of varying orthopedic and surgery journals.  

4. Research Articles Journal of Arthroplasty
Topical versus intravenous tranexamic acid in total knee arthroplasty
Knee Surgery, Sports Traumatology, and Arthroscopy
The comparative efficacies of intra-articular and IV tranexamic acid for reducing blood loss during total knee arthroplasty
Archives of Orthopaedic and Trauma Surgery
One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration
For all 3 of these articles, the complete citation can be found on the last slide.  
The first article is from the Journal of Arthroplasty titled: Topical versus intravenous tranexamic acid in total knee arthroplasty.
The objective of this study was to compare the IV use of TXA against the topical use of TXA in a primary unilateral TKA.
Using the exact same surgical technique, these two groups were compared, the only difference being that group A (consisting of 373 patients) received IV TXA and group B (consisting of 198 patients) received topical TXA.
They were also given the same IV fluids, volume expanders, and VTE prophylaxis with an INR goal of 2.0.  
The next study is from a journal titled the Knee Surgery, Sports Traumatology, and Arthroscopy. This study is similar to the first but includes not only the topical and IV groups, but also a placebo group.
This study included 150 patients, and the surgery was performed by the same surgeon, therefore keeping the technique and results consistent.
All patients underwent a unilateral TKA for degenerative arthritis.  
The third article is from the Archives of Orthopaedic and Trauma Surgery.
This is a meta-analysis of 31 clinical trials that used various methods of TXA to see the effect of blood loss along with rates of transfusion and thromboembolic events.
Again, for these studies, a primary unilateral TKA was completed and comparisons in each study were made to either a placebo or no treatment. 
This article does point out that there are many factors that can exclude a patient from being a candidate for IV administration for TXA such as cardiac disease or previous DVT. Because of this, topical administration may be a better route for these patients.  

5. Rationale for Article Selection
Journal of Arthroplasty
Compares topical use versus IV use of TXA
Knee Surgery, Sports Traumatology, and Arthroscopy
Compares topical, IV, and placebo
Archives of Orthopaedic and Trauma Surgery
Compares multiple trials of topical versus IV use of TXA
Journal of Arthroplasty 
This article was used because the main objective was to compare the effectiveness between the topical and IV use of tranexamic acid in a TKA, which is the same basis as the PICO question. There is no comparison to a placebo or any other treatment. The surgical technique was exactly the same in each case as well as the postoperative VTE prophylaxis.  
Knee Surgery, Sports Traumatology, and Arthroscopy 
This next study was chosen because not only does it compare topical versus IV TXA as the previous study, but it also utilizes a placebo. This shows whether TXA is effective at reducing total blood loss but itself as well as if topical TXA is more effective than IV use. Again, the surgical technique is the same, but the benefit to this study, is that all 150 surgeries were completed by the same surgeon.  
Archives of Orthopaedic and Trauma Surgery 
This last article relates to the PICO question because it compares multiple controlled trials conducted to study the effects of IV versus topical TXA on total blood loss. A total of 31 studies were compared. 

6. Study Identification Journal of Arthroplasty Post-op Topical IV Hbg
Prospective clinical trial
Comparing: IV TXA versus topical TXA
580 total patients divided into one of 2 groups
Data reported using means, standard deviations, frequencies, and percentages
Post-op
Topical IV
Hbg
11.4
11.1
Transfusion
2.4%
Change in Hbg
16.2%
20.1%
The study comparing the IV use of TXA versus topical application was a prospective clinical trial.
After approval from a review board, 580 patients were followed for a 12 month period at a joint center.
Participants were either in group I and given IV TXA by surgeon A or in group II and given topical TXA. 
The data was reported using means and standard deviations for the quantitative data and frequencies and percentages for the qualitative data.
The continuous variables were compared using a two-tailed t-test. For the categorical variables, a Fisher's exact test was used.  
This study concluded that on post-operative day one, the Hbg was higher (11.4) in the patients who received topical TXA  versus 11.1.
In the IV group the drop in Hgb was an average of 2.8 and in the topical it was only 2.2.
This means that the average change in Hgb was lower at 16.2% compared to the IV group at 20.1%.
One remarkable note is that the group who received topical TXA received no transfusions after surgery compared to the 2.4% of IV TXA patients.
According to this study, topical TXA reduces bleeding more effectively 

7. Study Identification
Knee Surgery, Sports Traumatology, and Arthroscopy
Prospective randomized clinical trial
Comparing: IV TXA, topical TXA, and placebo
150 patients divided evenly between groups
Kruskal-Wallis and Tukey's test used
Post-o IV
Topical
Placebo
Mean TBL
528ml
426ml
833ml
Transfusion rate
34%
20%
94%
PRBCs
273.6ml
129.6ml
920.8ml
drop Hbg
1.6
1.8
2.0
This study of 150 unilateral TKA is a prospective, randomized clinical trial as was the previous study.
Patients were randomly placed into either the IV, Intra-articular, or placebo group using a number list.
50 patients were in each category.
All patients were followed postoperatively for 2 months.  
To measure blood loss, Hbg levels, and transfusion levels, a Kruskal-Wallis test was used. Tukey's test was used to test the null hypothesis. 
The mean blood loss was as follows: 528ml for IV, 426ml for topical, and 833ml for placebo.
As for the rate of transfusion: the percentage that required a transfusion were 34% for the IV group, 20% for the topical group, and 94% for the placebo group.
The amount of PRBCS also differed and were 273.6ml in IV 129.6ml in topical and 920.8ml in placebo.
Post op Hbg decreased by 1.6, 1.8, and 2.0.
In this study, the results show that the utilization of TXA reduced blood loss compared to the placebo.
They also show that TXA is more effective topically than IV to reduce blood loss. 

8. Study Identification Archives of Orthopaedic and Trauma Surgery
Meta-analysis of randomized controlled clinical trials
31 total studies reviewed
Reviewed within the guidelines of the Cochrane Handbook for the Systematic Review and Meta-Analysis of Interventions
Studies used multiple statistical analysis including:
Chi-squared test
Mantel-Haenszel method
I2 statistic method
Fixed-effect model
This article is not a study in itself but a meta-analysis of 31 randomized controlled clinical trials. two studies were triple blind, 20 were double blind, and 3 were single blind. 
As stated in the article it was done within the guidelines described in the "Cochrane handbook for the systematic review and meta-analysis of interventions" 
Because there are many studies involved, the types of statistical analysis used depends on the study reviewed.
Some include the Chi squared test, Mantel-Haenszel method, I squared statistic, and fixed-effect model. A funnel plot was made for the outcome of total blood loss and the number of patients requiring transfusion.  
Comparing all 31 studies, there was significant reduction in total EBL for both groups compared to the control.
There was, however, no comparative significance in EBL between IV and intra articular use

9. Ethical Considerations
Social Value
Scientific Validity
Fair Subject Selection
Favorable Risk-benefit Ratio
Independent Review
Informed Consent
Respect for Subjects
According to the National Institute of Health there are 7 principles to consider when looking at the ethical aspect of a study. These are social value, scientific validity, fair subject selection, favorable-risk benefit ratio, independent review, informed consent, and respect for subject.  
social value 
A TKA is a very common orthopedic procedure. In fact According to Shemshaki et al. it is expected to reach 3.48 million by However, it is also associated with a high blood loss during surgery. Some studies estimate around 1,000 ml of total blood loss. In many cases this requires blood transfusion post-operatively. Because blood loss, hemodynamic instability, and transfusions can be problematic, surgeons are looking for ways to decrease blood loss during surgery 
scientific validity 
TXA can reduce total EBL without an increased risk for thromboembolic complications according to some small current clinical trials. As mentioned before some studies show reduction in EBL by a mean of 500ml in a TKA and reduction for the need of transfusion by 45% 
fair subject selection 
In the studies selected for this presentation, all participants are reviewed by a board. They are excluded based on any cardiac history or contraindication to TXA. It is not mentioned specifically whether any race or ethnic origin is included or excluded, possibly since that is not the basis for this study or the question being asked. This is, however, and important ethical decision to be considered.  
favorable risk-benefit ratio 
patients are excluded for the drug itself if they have had previous DVT, PE, MI, stroke, subarachnoid hemorrhage or other bleeding disorders 
Most studies exclude patients from the trials for these reasons regardless if they are for the placebo as well.  
independent review 
In order to avoid a conflict of interest, an independent review is important. None of the studies mentioned specifically state whether or not they are reviewed independently, however, in order for it to be more valid it most likely is. 
informed consent 
For a clinical trial each patient would need an informed consent stating they are voluntarily participating in the trial and have been given full disclosure. They may not know which treatment they will be receiving, as with a blind study, but they need to know all possible outcomes. The must be deemed competent and understand all aspects of what is being told to them. This is one of the most important ethical considerations. 
respect for subjects 
Lastly, each participant must be respected. Other that for the study data itself, this is one of the reasons that they are followed after the study is completed. One study included in the presentation the participants were followed for an entire year to ensure that their well-being was intact. This is also why they are allowed to leave a study at any point. Patients information is kept confidential for their protection.  

10. Strength, Quality, and Credibility
Journal of Arthroplasty
Published in 2015
Used to inform
Written by experts from the Bone and Joint Center at the Magee Womens Hospital of the University of Pittsburgh Medical Center
Current cited references
Conflict of interest statement available with journal subscription
This article was current article meant to inform the reader, and published in a reputable journal in It is clear that it was written by physicians that are experts in their field.
The authors are affiliated with the Bone and Joint center at the Magee Womens Hospital of the University of Pittsburgh Medical Center.
There appears to be no bias with no advertisements or sponsorships identified. All material is clearly referenced with current sources and working hyperlinks.
A conflict of interest statement is also available online, however, a subscription to the journal is needed to view it. 
Based on this criteria and the information provided by the study, this source would provide a reliable contribution to EBP 

11. Strength, Quality, and Credibility
Knee Surgery, Sports Traumatology, and Arthoscopy
Published in 2013
Used to inform and explain
Authors associated with the Department of Orthopaedic Surgery at the Samsung Medical Center and the Department of Orthopaedic Surgery at the National Health Insurance Corporation Ilsan Hospital
Current cited references
This article was published in 2013 in a reliable journal.
Although it is a few years older than the first study, the authors still sought to provide pertinent information to inform and explain the reader.
The authors do not specify their educational background, but they are associated with either the Department of Orthopaedic surgery at the Samsung Medical Center or the Department of Orthopaedic surgery at the National Health Insurance Corporation Ilsan Hospital.
No persuasion to or bias in the article is noted.
Current, reputable sources are noted. 
With this current information, this article would also make a contribution to EBP 

12. Strength, Quality, and Credibility
Archives of Orthopaedic and Trauma Surgery
Published in 2015
Studies reviewed were published between
Used to inform
Authors affiliated with prestigious medical facilities and universities
Current cited references
For this meta-analysis, it was published in 2015 and reviewed 31 studies between the years ; giving it all current, relative data.
This article serves to inform the public, same as the first 2. All of the authors are associated with various medical facilities and universities.
No bias or partnership appears to be evident. Each source is accurately cited and current.  
This study makes a contribution to EBP based on all of the criteria provided.  

13. Relevancy and Implications to Practice
Reduce total blood loss
Prevents post-operative complications
Decreases rate of transfusion
Improves patient outcomes
Studies show significant measureable, objective data proving the positive effects of TXA
The findings from these studies have the potential to be significant for future medical practice.
This is especially true because it has the possibility to prevent blood loss in a complicated, but common orthopedic surgeries and improve patient outcomes.
The results thus far are reliable and consistent with other studies that are similar. The content measures observable, measurable data than can be repeated in other studies which is important.  
 At this point, with the need for more studies looking at the possibility of VTE complications, it needs to be communicated at the professional level. There is not enough evidence to back up a policy and further it to a standard level of care to make the majority of orthopedic surgeons make it their standard of practice 
The use of TXA has the potential to decrease the post-operative complications of blood loss after a TKA. Overall this has the potential to greatly benefit this type of surgical patient, as well as many other types of orthopedic candidates.  
Not only does acute blood loss hold the potential for complications but the transfusion of blood products is also known to increase post-operative complications.  
Looking at the studies shown, the significance in the difference in blood loss, drop in Hgb, and lack of need for transfusion shows a significant improvement with the use of TXA. Intra-articular use of TXA showed a greater improvement in reducing blood loss, and with further studies may prove to still be an option if there is a previous contraindication for the IV form. 
Looking at generalizability, we cannot ignore the strength and quality of what these studies have already shown us.  
The quality and safety of this practice change is already happening on the individual level. It now needs to be looked at a higher level. With the potential for VTE events however, more studies may need to be conducted and reviewed before it is made a policy or standard of care. 

14. Potential Barriers on Utilization of Findings
Medical History
Cost
Difficulty making a standardized policy
Lack of research on side effects
medical history 
There are many restrictions for utilization for TXA regarding patient medical history including previous cardiac problems. This also includes any bleeding disorders or history of any type of thrombolytic event. However, with further research, topical use of TXA may not be contraindicated because it is not systemically absorbed 
Cost 
The cost of the medication, whether it is topical or IV may be financially more expensive than other fluid expanders or medications. Certain insurances may also not cover it. 
Difficulty making a standardized policy 
Surgeons tend to be particular in the way they practice down to the very last detail. Although they keep up on current research, orthopedic surgeons still operate in a way they are comfortable. Just because one surgeon would be willing to use TXA as their standard of care, unless contraindicated or course, does not mean another would.  
lack of research on side effects 
One of the biggest concerns mentioned in the studies that were reviewed was the potential for increased risk for thrombolytic events. Although those particular studies showed not specific increased risk, it is still a potential concern. This was one of the reasons that topical TXA was mentioned 

15. Additional PICO Questions
In patients receiving tranexamic acid, compared to those who do not, are they at an increased risk for developing a thrombolytic event?
For patients that are not a candidate for IV TXA because of previous medical history, compared to those that have no contraindicated history, just as at risk for complications with topical tranexamic acid?
For patients having other orthopedic procedures, compared to just a total knee arthroplasty, have a better outcome with less total estimated blood loss with tranexamic acid?
For patients receiving tranexamic acid, compared those who are not, are there less post-operative complications?
In patients receiving TXA, compared to those who do not, at an increased risk for developing a thrombolytic event? 
For patients that are not a candidate for IV TXA, compared to those that have no history, just as at risk for complications with topical TXA? 
For patients having other orthopedic procedures, compared to just a TKA, have a better outcome with less total EBL with TXA? 
For patients receiving TXA, compared to those who are not, are there less post-operative complications?

16. Conclusions
In patients undergoing a total knee arthroplasty, does the use of tranexamic acid intra-articularly versus receiving the standard divided dose of intravenous tranexamic acid reduce bleeding more effectively?
YES!!
Base

17. References
Emanuel, E., Abdoler, E., & Stunkel, L. (n.d.). Research ethics: How to treat people who participate in research. Retrieved from
Hamlin, B. R., DiGioia, A. M., Plakseychuk, A. Y., & Levison, T. J. (2015). Topical versus intravenous tranexamic acid in total knee arthroplasty. The Journal of Arthroplasty, 30,
Seo, J.-G., Moon, Y.-W., Park, S.-H., Kim, S.-M., & Ko, K.-R. (2013). The comparative efficacies of intra-articular and IV tranexamic acid for reducing blood loss during total knee arthroplasty. Knee Surgery, Sports Traumatology, and Arthroscopy, 21,
Shemshaki, H., Amin Nourian, S. M., Nourian, N., Dehghani, M., Makhtari, M., & Mazoochian, F. (2015). One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Archives of Orthopaedic and Trauma Surgery, 135,
VHA Pharmacy Benefits Management Services, Medical Advisory Panel, VISN Pharmacist Executives, & National Surgery Offic. (2014). Clinical recommendations for using tranexamic acid for reducing blood loss and transfusion requirements in patients undergoing total knee or total hip arthroplasty December Retrieved from in_TKA_or_THA_Clinical_Recommendations.pdf