1. Anti-Xa versus aPTT for therapeutic Anticoagulation
Ashley Bade

2. Anti-Xa or aPTT? Why is this important?
When do we use these tests and which one is better?
PICO: For patients receiving intravenous heparin infusions, is therapeutic anticoagulation achieved faster when monitoring anti-factor Xa levels compared to monitoring activated partial thromboplastin levels?
This power point is meant to explore the topic of therapeutic anticoagulation using different methods of lab testing.
Patients in the hospital setting sometimes receive anticoagulant therapy intravenously which requires testing to determine when the anticoagulant has achieved a therapeutic level, and also ensure that anticoagulation dosing is maintained at a safe level.
Patient’s who receive anticoagulant therapies are prescribed these medications because they are at a higher risk for developing blood clots, so It is also important to achieve therapeutic anticoagulation as quickly as possible so that clots do not develop.
It is also important to continue monitoring these levels so that the patient will benefit from the medication, without experiencing harmful side effects, such as bleeding which can occur when levels are too high, or clotting when levels are too low.
Two of the most common lab tests available for monitoring therapeutic anticoagulation include the Anti-factor Xa level and the activated partial thromboplastin level. Traditionally, the activated partial thromboplastin level has been used to determine therapeutic anticoagulation, with the anti-Xa level becoming more popular as many facilities choose to use this level for determining anticoagulation status. Because there are different lab tests available to determine therapeutic dosing of intravenous heparin, it would be helpful to determine the most effective testing to improve patient outcomes.
Therefore, the question I have developed is as follows: For patient’s receiving intravenous heparin infusions, is therapeutic anticoagulation achieved faster when monitoring anti-factor Xa levels compared to monitoring activated partial thromboplastin levels?

3. Search Methods Search Engines: Cinahl, PubMed, and Google Scholar
Search Terms: Anti-Xa, Anti-Factor Xa, aPTT, Activated Partial Thromboplastin, Unfractionated Heparin, Therapeutic Anticoagulation
Results of Search: Each search engine produced roughly 20 or less results that were published within the last 5 years, and peer-reviewed.
The search engines I used to find the articles for this presentation were Cinahl, PubMed and Google Scholar.
Google Scholar did not produce very specific results so the other search engines were used for the primary collection of information and articles.
I used search terms that were simple and primarily the names or abbreviation of the specific lab tests I wanted to research, such as Anti-Xa, Anti-factor Xa, aPTT, activated partial thromboplastin time, unfractionated heparin, and therapeutic anticoagulation.
Both the Cinahl and Pubmed search engines produced about 20 or less results that were published within the last 5 years and peer-reviewed.
Also, many of the articles within the results did not look primarily at the distinction between the Anti-Xa and the aPTT tests, but at the practice of using lab tests to evaluate anticoagulant therapies. There were roughly about 10 or less that focused on the comparison of the Anti-Xa and aPTT tests in the use of intravenous heparin therapy.

4. Chosen Articles Study A
Activated Partial Thromboplastin time versus Anti-factor Xa Heparin assay in monitoring unfractionated heparin by continuous intravenous infusion
Guervil, D.J., Rosenberg, A.F., Winterstein, A.G., Harris, N.S., Johns, T.E., & Zumberg, M.S. (2011). Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. The Annals of Pharmacotherapy 45(8), pp Doi: /aph.1Q161
Study B
Discordant aPTT and Anti-Xa values and outcomes in hospitalized patients treated with intravenous unfractionated heparin
Price, E.A., Jin, J., Nguyen, H., Krishnan, G., Bowen, R., Zehnder, J.L. (2013). The Annals of Pharmacotherapy 47(), pp Doi: /aph.1R635
The 2 articles I chose to use for this presentation look directly at the comparison of the activated partial thromboplastin time and the anti-Xa test specifically when determining therapeutic anticoagulation with the use of intravenous heparin therapy.
The first article is titled “Activated partial thromboplastin time versus anti-factor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion” and this article was published in The Annals of Pharmacotherapy.
The second article is titled “Discordant aPTT and Anti-Xa values and outcomes in hospitalized patients treated with intravenous unfractionated heparin” which was also published in the The Annals of Pharmacotherapy.
For the purpose of this presentation I will refer to the first study as “Study A”, and the second study as “Study B”.

5. Rationale for Selection
The articles directly explore the use of the activated partial thromboplastin time and anti-Xa lab tests
The articles describe the indications for these lab tests in heparin therapy for therapeutic anticoagulation.
The two articles I choose focused directly on the comparison of the anti-Xa lab test and the activated partial thromboplastin time, or aPTT test, and their indication for use in heparin therapy for therapeutic anticoagulation. These articles focused on the pros and cons of each test and how they relate to patient safety, patient outcomes, and how they can improve heparin therapy for anticoagulation.

6. Theory Do these studies incorporate theory?
The journal articles did not use any theory based information for the content. These studies focused on the use and measurement of an intervention in a retrospective manner, instead of the application of a theory in practice with observation of results.

7. Study Type and Design
Study A: single-center, retrospective, observational cohort study
Review of electronic and paper medical records
Compared use of anti-Xa lab values and aPTT values to determine therapeutic anticoagulation status
Study B: retrospective observational study
Comparison of laboratory data from which the samples were obtained simultaneously to determine consistency in anticoagulation status
In Study A:
This study was a single-center, retrospective, observational cohort study. This means that the records from a small group of patients who received the same treatment were studied to analyze their lab tests results after they had received those treatments. The patients included in this study either received the aPTT test, or the anti-Xa test (Guervil, Rosenberg, Winterstein, Harris, Johns, & Zumberg, 2011, pp )
In Study B:
This study was also a retrospective observational study. This study involved a larger number of patient medical records included over a shorter period of time, during which all patients had received both the aPTT test and anti-Xa test (Price, Jin, Nguyen, Krishnan, Bowen, & Zehnder, 2013, pp ).

8. Method and Findings Study A 50 selected patients from each group
Review of medical records
Anti-Xa achieved therapeutic anticoagulation faster than the aPTT test
Study B
539 selected patients
Only 40% of patients had concordant aPTT and Anti-Xa
Results still unclear as to optimal role that each method may play in monitoring heparin in high-risk patients
***Methods and findings***
Study A: This study involved a review of both paper and electronic medical records from 172 patients between May of 2005 and September 2009 at an 852-bed academic medical center. The patient records were then split into two groups by random number generation to produce 50 patients for each group. The first group received intravenous heparin between May 1, 2005 and April 31, 2007, and were monitored using the aPTT test. The second group received intravenous heparin between June 1, 2007 and September 1, 2009 and were monitored using the Anti-Xa test. The study then evaluated the time it took for each patient to achieve therapeutic anticoagulation using the aPTT and Anti-Xa lab results comparatively. The collected data was analyzed using statistical analysis. The results indicated that patients were able to achieve therapeutic anticoagulation faster using the Anti-Xa assay than the aPTT test, they were able to maintain therapeutic levels of heparin a longer time, and required fewer adjustments in dosage and repeated tests (Guervil, Rosenberg, Winterstein, Harris, Johns, & Zumberg, 2011, p. 865)
Study B: This study involved a review of medical records of 539 patients from February 2009 to August 2009 at Stanford Hospital. All samples were drawn simultaneously and per hospital standard protocol. Each patient received the aPTT test and the Anti-Xa heparin assay to monitor heparin therapy, and then compared for indications of anticoagulation status. The results indicated that the data pairs of anti-Xa levels and aPTT levels were discordant most of the time with 18% of data pairs having a low aPTT value compared to the anti-Xa level, 42% having a high aPTT value compared to the anti-Xa level, and with only 40% having a concordant aPTT and anti-Xa level. After further review of the data collected and medical records used, analysis was further broken down to examine the outcomes based on the comparison of aPTT values and how they compare to the simultaneous anti-Xa level. The study specifies though that the aPTT will be prolonged when the patient has low coagulation factor levels and compromised hemostatic system, and prolonged in the presence of elevated factor VIII or fibrinogen levels, and that the use of warfarin can also lengthen the aPTT. The study then indicates that the important distinction between the aPTT test and the anti-Xa test is that the anti-Xa directly measures the functional activity of heparin in inhibiting coagulation factors making it a more reliable source of anticoagulant status with less interfering factors. The conclusion of the study does however note that the anti-Xa level does provide a estimate of heparin anticoagulation status but that the aPTT reflects both baseline anticoagulation status and the impact of anticoagulants. The authors go on to note that with these results, if anticoagulation is indicated, monitoring of both aPTT and anti-Xa levels may be useful in optimizing risk versus benefit and that further study is needed to clarify the optimal role that each method may play in monitoring heparin therapy (Price, Jin, Nguyen, Krishnan, Bowen, & Zehnder, 2013, pp ).

9. Ethical Considerations
Patient safety and prevention of adverse events
Improved patient outcomes
Ethical considerations of both studies involve the the importance of honest reporting of data. In this case, the appropriate reporting of data results in better practices and improved patient outcomes. Since heparin is considered a high-risk medication, it is considered ethically important to ensure that patient safety is maintained through honest reporting to prevent adverse outcomes such as unintentional bleeding that results in harm to the patient.

10. Strength of Study Study A & B Peer-reviewed journal
Limitations of study
Contributing/competing factors
Failure to maintain protocols
Retrospective
Study size
Strengths of study
Credibility of authors
Both of the articles were published by the Annals of Pharmacotherapy which is a peer-reviewed journal that works to establish better health care practices through research and literature reviews.
The primary author of the Study A is David Guervil, and holds a Doctorate of Pharmacology with a specialty in infectious diseases and antimicrobial management at the Memorial Hermann Hospital of Texas (Memorial Hermann Hospital, 2015). This study was a smaller single-center study that does limit it’s applicability as it would need to be repeated on a larger scale to reproduce the results or disprove them. The authors also point out other study limitations that include: unknown factors that could have influenced results, that important data could have been missing from patient records, and that bias could have been introduced if there were difference in illness severity between the two groups. The authors also note that exposure to clopidogrel in the anti-Xa assay group could have results in increased bleeding risk, which was not substantiated in the descriptive analysis. The authors suggest a large, multicenter randomized trial to further substantiate the results. That being said, the strength of the study is noted in it’s identification of the different in time of achieving therapeutic anticoagulation between the two tests. According to the authors, this study indicated that the odds of reaching therapeutic anticoagulation at 24 hours were 3.5 times higher for anti-Xa patients than for aPTT patients, which indicates a significant difference (Guervil, Rosenberg, Winterstein, Harris, Johns, & Zumberg, 2011, pp ).
The primary author of Study B is Elizabeth Price who is a clinical associate professor of medicine-hematology at the Stanford School of Medicine with multiple published articles pertaining to hematology (Stanford School of Medicine, 2015). The authors note the limitations of this study to include the lack of knowledge regarding poor sampling or need to repeat assays, and the fact that it is a retrospective study and that a prospective study could confirm results in the future. The study does note a major strength of the study as having a large sample size with extensive follow-up data (Price, Jin, Nguyen, Krishnan, Bowen, & Zehnder, 2013, p. 156).
Additionally, it would be important to note that there are other variables that may or may not have been considered that could influence changes in therapeutic anticoagulation and lab values. These variables might include patient diagnoses that might alter coagulation such as factor deficiencies or excesses, or other blood disorders and coagulopathies, co-therapies that may contribute to or inhibit the effectiveness of anticoagulant medications, and the failure of proper specimen collection practices including specimen handling and storage.

11. Quality of Study Peer reviewed
Retrospective observational cohort study
No treatment
Population defined
Exclusion criteria
Population size
Authors noted strengths and weaknesses of results, and limitations
Both studies were published by a peer reviewed journal which indicates that it was reviewed and analyzed for deficits and strengths in study type and results, that it is relevant and appropriate, and is scholarly in content (University of Texas Libraries, 2015).
Additionally, both studies were retrospective in that they observed data already obtained that was not effected by a treatment or intervention introduced by those conducting the study. This indicates that both studies fall under a 2b level of evidence in the hierarchy of evidence (Oxford Center for Evidence-based Medicine, 2014).
The population was also clearly defined with identified exclusion and inclusion criteria and how those factors were determined and why. Population size was also identified and noted for its implication of strength or weakness in both studies.
The authors of both studies also identified additional strengths and weaknesses, as well as limitations of each study, and how they could contribute to the results and what recommendations they would make towards future investigation.

12. Credibility and Criteria
Development of protocols
Inclusion criteria of studies
Age, diagnoses, compliance with protocols
Reliability of data
EBP contribution
Study A: The patients were between the ages of 18 and 89. Exclusion criteria included the use of heparin therapy for less than 24 hours, treatment interrupted for more than 10 hours, and inadequate compliance with protocol titration instructions which was defined as a deviation of more than 25% of the protocol elements during the total times of heparin therapy. The same protocols were used for both lab testing criteria throughout the study, and were developed based on previously published weight-based heparin dosing nomograms and recommendations of clinical practice guidelines at the time of implementation (Guervil, Rosenberg, Winterstein, Harris, Johns, & Zumberg, 2011, pp ).
Study B: The patients were aged 18 and older. Exclusion criteria included patients who received anti-Xa testing incorrectly (such as in patients receiving low molecular weight heparin instead of unfractionated heparin). Patient records were also reviewed for baseline aPTT values and/or other anticoagulation values within the 7 days prior to starting heparin therapy, the indication for heparin therapy, the presence of active malignancy, the use of warfarin therapy on day of blood-draw, the presence of transaminases or bilirubin above normal range within 7 days before the data pair was analyzed, the survival to 30 days following the first aPTT/anti-Xa data pair, major bleeding within 21 days following the first data pair, or a new thrombotic event occurring within 21 days following the first data pair (Price, Jin, Nguyen, Krishnan, Bowen, & Zehnder, 2013, p. 152).
Both of these studies provided comprehensive inclusion criteria and analysis adding to the credibility of the studies, and both contribute to evidence based practice in that the primary goal is to seek out the best therapeutic anticoagulation monitoring to improve outcomes in patients receiving intravenous heparin.

13. Relevance to Practice Patient outcomes Costs
Anticoagulation achieved faster
Anticoagulation better maintained
Costs
Decreased frequency of testing and dose adjustments
In regards to relevance to practice, the differentiation of best practice for achieving therapeutic anticoagulation has many implications. When anticoagulation is achieved faster, patient outcomes are improved as therapy can be maintained at appropriate dosing, and adequately maintained for better prevention of unexpected bleeding or coagulation events. This will overall decrease the risk to the patient and prevent adverse events from occurring.
One argument against the anti-Xa test is the increased cost compared to the aPTT test. However, it could also easily be argued that if patients are achieving anticoagulation faster, that the increased cost is negated by the decreased time it takes to achieve therapeutic status. Additionally, less frequent monitoring of lab values will be needed and less dosing adjustment will be required.

14. Relevance to Practice
Better therapeutic management in patients requiring anticoagulation
Therapeutic levels achieved faster and better maintained
Policy standards
Collaboration
Resistance
As previously mentioned, if therapeutic anticoagulation is achieved faster, better management to prevent adverse outcomes can be maintained.
The relative switch to the anti-Xa lab value would likely require a policy change, including the introduction of a new nomogram based on facility approved lab ranges and heparin titration with and without bolus amounts. This would involve the collaboration between nurses, doctors, and pharmacists in developing the policy and ensuring understanding of use of the nomogram that would be put in place. The implementation of the anti-Xa lab value and nomogram may be met with some resistance given the historical use of the aPTT lab values and nomograms, and that this is a relatively new approach with less clinical research validating its use compared to the aPTT test.

15. Relevance to Practice
Frequently prescribed therapy in hospital settings
High risk medication
Future PICO questions
Lastly, the relevance of this question is further cemented in that heparin is a high risk medication with significant risk for adverse events if not appropriately managed. It is also a medication that is commonly prescribed in the clinical in-patient setting. In order to decrease risk of adverse events and improve patient outcomes, it is important to establish the best evidence based practice to achieve therapeutic anticoagulation as fast as possible, and maintain it at a safe level.
Future PICO questions that could be derived from this might include the effects of specific diagnoses on aPTT lab values and anti-Xa lab values respectively.

16. Conclusion Conflicting results between anti-Xa and aPTT values
Further studies need to be conducted
Based on the studies I have reviewed, further study may be required to determine which lab test is better in indicating therapeutic anticoagulation. That being said, initial results indicate that the anti-Xa lab achieves therapeutic anticoagulation faster than the aPTT test. Discordant results in anti-Xa lab values and aPTT lab values however indicate a need for further investigation as to the optimal role each lab may play in monitoring heparin use in hospitalized patients.

17. References
Guervil, D.J., Rosenberg, A.F., Winterstein, A.G., Harris, N.S., Johns, T.E., & Zumberg, M.S. (2011). Activated partial thromboplastin time versus antifactor Xa heparin by continuous intravenous infusion. The Annals of Pharmacotherapy 45(8), pp Doi: /aph.1Q161
Memorial Hermann. (2015). Residency and experiential program preceptors. Retrieved from
Oxford Center for Evidence-based Medicine. (2014). Oxford center for evidence-based medicine – Levels of evidence (March 2009). Retrieved from
Price, E.A., Jin, J., Nguyen, H., Krishnan, G., Bowen, R., Zehnder, J.L. (2013). The Annals of Pharmacotherapy 47(2), pp Doi: /aph.1R635
Stanford School of Medicine. (2015). CAP profiles: Elizabeth Price: Clinical assistant professor, medicine-hematology. Retrieved from
University of Texas Libraries. (2015). Peer reviewed journals. Retrieved from