Michael P Gulseth Anticoagulation Consulting, Inc.
Specializing in professional consulting to aid hospitals and health-systems optimize patient outcomes when using anticoagulants and avoid litigation
We Finally Have a Comparison of Factor Xa Inhibitor to Unfractionated Heparin Infusion Management Strategies
|Posted by gulseth.michael on May 13, 2022 at 6:00 AM||comments (3193)|
By Michael P Gulseth, Pharm. D., BCPS, FASHP
Wow, has it been a long time since I wrote a blog post…….
If you read my past posts or spoken to me, you know I’ve had serious concerns on how many were handling factor Xa inhibitor to heparin drip transitions. Some had recommended simply using aptt to manage the transition, such as this article:
That article had correctly stated the factor Xa inhibitors have a residual effect on heparin anti-Xa levels…..this is 100% correct. However, my concern from the beginning was this indicates some level of factor Xa inhibition meaning starting heparin immediately may or may not be a good idea. (And we later got data showing heparin anti-Xa levels tend to be linear with apixaban/rivaroxaban serum concdentrations.) I’ve had many, many patients who need to transition to heparin with acute kidney injury where the thrombosis risk to the patient is low, where this approach simply does not make sense in my mind.
We took a different approach. After we published this article
we developed a factor Xa inhibitor to heparin transition guideline that uses either heparin anti-Xa levels or drug specific apixaban/rivaroxaban anti-Xa levels as key drivers in decision making. Our goal was to avoid unnecessary heparin use in low risk situation where we very well may over-anticoagulate the patient, and only risk over-anticoagulation in the highest risk situations. (That is when we would use aPTT monitoring.)
We have now completed and published our comparison of this strategy to a hospital that used aPTT and started heparin when the next apixaban/rivaroxaban dose would be due. We would encourage you to read our article:
We are so excited to share these results with everyone. We are aware of no other study that has compared large cohorts of patients looking at different strategies to manage this dilemma. While this is not the final word on this topic, we feel these results are promising and do not endorse routine use of aPTT to manage this transition in every patient. Ignorance of residual apixaban/rivaroxaban may not be bliss……
Archived Blog Archive
|Posted by gulseth.michael on May 12, 2022 at 5:00 PM|
I'd negleted my site and had thousands of undwanted spam comments. I've deleted the old blog postings, but will repost all below for any interested and disable comments for this post. I hope to post a new blog soon.
Archived blog posts
Is 4-factor Prothrombin Complex Concentrate (4F-PCC) or Andexxa® Better to Reverse Xa Inhibitor Bleeding?
Posted by gulseth.michael on August 6, 2019 at 1:05 PM
By Jenna Cariddi, Pharm D Student Pharmacist
Edited by Michael P Gulseth, Pharm. D., BCPS, FASHP
A current controversial topic amongst anticoagulation management providers is what is the best agent to use for the reversal of bleeding from oral Xa inhibitors. This is a debatable topic because many anticoagulation reversal guidelines were published prior to the approval of andexanet alfa and because there have been no studies comparing andexanet alfa to other therapies such as 4-factor prothrombin complex concentrate (4F-PCC).
Andexanet alfa was approvedby the FDA in May 2018 as a reversal agent for bleeding in patients on apixaban or rivaroxaban(1). This was exciting news to the anticoagulation world but concerns regarding thrombosis rates, lacking data in specific treatment areas, and price ultimately resulted in many hospitals not placing the drug on formulary.
Prior to the approval of andexanet alfa, 4F-PCC has been the off-label treatment of choice for the reversal of factor Xa inhibitor associated bleeding. Due this, experience was gained in use 4F-PCC for direct oral anticoagulant (DOAC) reversal.
Dosing 4F-PCC for factor Xa inhibitor bleeding reversal using weight-based (50 units/kg) or fixed dosing (2000 units) has also been debated as to which is best. The recent consensus statement of the Anticoagulation Forum (AC Forum) states they prefer fixed dosing due to it having been studied in patients with bleeding from factor Xa inhibitors, simpler for the pharmacy and provider ordering it, and the lower cost (1).
This lack of definitive data on optimal DOAC reversal has led to controversy within guidelines.
2017 ACC Management of Bleeding in patients on anticoagulants guidelines state:
- 4F-PCC is a reasonable option for emergency bleeding reversal in patients using oral direct factor Xa inhibitors(2).
2018 ACC Guidance for anticoagulation reversal update from 2017 states:
- First line for edoxaban reversal is 4F-PCC
- First line for apixaban and rivaroxaban reversal is andexanet alfa dose dependent on apixaban/rivaroxaban dose and time since last dose (3).
2019 AHA/ACC/HRS update of Afib management guidelines states:
- Andexanet alfa can be useful to reverse life threatening bleeding of rivaroxaban and apixaban (4).
2018 American Society of Hematology (ASH) guidelines for management of VTE state:
- They SUGGEST using either 4F-PCC in addition to stopping the Xa inhibitor or just stopping the Xa inhibitor alone (for life threatening bleeding during treatment with Xa inhibitor for VTE treatment) – also SUGGEST using andexanet alfa in addition to stopping the Xa inhibitor rather than no andexanet alfa – They state they have no recommendation for one approach over the other (5).
2019 AC Forum comprehensive guidance statement on DOAC reversal:
- For patients with apixaban or rivaroxaban associated major bleeding they suggest using andexanet alfa – if andexanet alfa not available then they suggest using 4F-PCC (1).
Considering the variability of these statements, we’d encourage health-systems to evaluated the pros and cons of each agent prior to making a decision on formulary status/use.
Andexanet alfa pros:
-FDA approved for the reversal of apixaban and rivaroxaban
-Logical mechanism of action for reversal of factor Xa bleeding
-Proven anti-factor Xa activity reduction by more than 90%
-Rapid onset/offset; within 2-5 minutes of IV bolus dose the generation of thrombin was fully restored
-Sustained results when given IV infusion after bolus (but only when infusion is running) (6)
Andexanet alfa cons:
-Relatively short duration of action necessitating bolus followed by IV infusion
-Optimal length of infusion is largely unknown, particularly in the surgical population
-Lack of surgical data; not tested for the reversal of surgical bleeding; unknown if 2-hour infusion is enough for long surgeries
-Higher than expected thromboembolism rate in patients within 30 days (1)
-Complex dosing depending on DOAC dose and time since last dose
-Potential prothrombic effect from inhibiting activity of Tissue Factor Pathway Inhibitor (TFPI), increasing tissue factor-initiated thrombin generation
-Time consuming preparation; requires many vials and preparation time is not ideal when emergent use is needed
-Unable to use heparin during surgical procedure following administration of andexanet alfa due to it neutralizing heparin’s effect (7)
-Has been available longer with more experience
-Recommended dosing does not depend on DOAC dose and time since last dose
-Theoretical longer duration of action (7)
-Not FDA approved for reversal of anticoagulation with DOACs
-No safety or efficacy data on using 4F-PCC for factor Xa bleeding reversal
-Unable to be used in HIT patients due to presence of heparin in small variable amounts
-Does not reliability lower Xa activity in trials
-In theory, drug that is attempting to be reversed would inhibit the factor Xa generated from the 4F-PCC
-Thrombotic risk (unknown if better or worse than the alternative)
In conclusion, at this time there is no definitive answer on which is the better agent to use. Not all hospitals have added andexanet alfa to their formulary and this is due to the current lack of definitive data and high cost. There may be situations when one is preferred over the other.
There is a Phase IV clinical trial currently in progress that will evaluate the use of andexanet alfa vs standard of care in ICH patients taking a DOAC. Although this is not a direct comparison to treatment with 4F-PCC specifically, it will hopefully give us more conclusive data.
Below is a link to this clinical trial:
1. Cuker A, Burnett A, Triller D, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol. 2019; 94: 697-709.
2. Tomaselli GF, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants. Journal of the American College of Cardiology. 2017;70(24)3042-3067.
3. Tomaselli GF, et al. 2018 Update on 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants. Journal of the American College of Cardiology. 2017 [2018 July update Guidance for Anticoagulation Reversal];70(24)3042-3067
4. January CT, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. Circulation. 2019;140:125-151
5. Witt DM, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Advances. 2018;2:3257-3291.
6. Siegal DM, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015; 373:2413-2424.
7. Dager WE, Gulseth MP, Nutescu EA. Anticoagulation Therapy: A Clinical Practice Guide. 2nd edition. Bethesda: American Society of Health-System Pharmacists; 2018.
8. Shaw JR, Siegal DM. Pharmacological reversal of the direct oral anticoagulants-A comprehensive review of the literature. Res Pract Thromb Haemost. 2018 Apr; 2(2):251-265.
The Need for Baseline anti-Xa Levels when Monitoring Heparin in the Direct Oral Anticoagulant Era
Posted by gulseth.michael on March 5, 2019 at 6:00 AM
By Michael P Gulseth, Pharm. D., BCPS, FASHP
DOAC to heparin transitions have become one of the more challenging issues in the modern era of anticoagulation management. I am regularly contacted (1-2 times per month) by colleagues for advice how to handle this. While even we don’t have all the answers, we have learned a few things from the literature.
Probably the most important article published on this topic is Macedo KA, et. al. I have a link to the artilce in the reference section below. Key findings included:
• Studied 50 patients taking apixaban or rivaroxaban who had heparin anti-Xa levels measured before or after initiating UFH
• Residual apixaban and rivaroxaban was found to affect the anti-Xa monitoring for up to 96 hours
• 25% of patients developed AKI
• Of the 28 patients were transitioned from apixaban or rivaroxaban to UFH, analysis of the initial heparin anti-Xa levels showed a supratherapeutic result (>0.7 units/mL) in 69% of patients, therapeutic result in 24% of patients, and anti-Xa levels of <0.3 units/mL (subtherapeutic) in 7% of patients
• The authors recommended initiating UFH for patients at high risk for thrombosis once the heparin anti-Xa level was <1 unit/mL and <0.7 units/mL for patients at low risk of thrombosis, but acknowledging each case must be addressed based on underlying risk/benefit.
Another study recently published Billoir, et. al. looking at correlations of heparin calibrated Xa to the actual levels of rivaroxaban and apixaban. (link is below) This has validated, in my mind, the findings and recommendations of Macedo.
(Note, the articles above helped me realize it was unnecessary to draw drug specific levels in every patient…….heparin correlated anti-Xa can be adequate in some situations. Optimally, you'll want to know the correlations on your hospital's instrumentation.)
So, it became quickly apparent that baseline anti-Xa levels are needed in the direct oral anticoagulant (DOAC) era, just as we do baseline aptt levels. When one gets into patient safety principles, it is much easier to do everything the same way on every patient rather than relying on someone to remember to do something. Many hospitals in the country have moved to this practice.
Note, if there are good reasons to NOT draw a baseline Xa, it is okay to do so. However, I would mainly only recommend that in a patient who is transiting into a hospital already on a heparin drip; for that patient, it will not provide value. In fact, if done, you will need to take an active role that a level is interpreted correctly. (example, patient bolused at outside hospital and started on a drip and shipped in. Bolus was 2 hours ago; Xa comes back at 1……..you need to make sure the drip is NOT turned down in that situation…..think about the kinetics…..)
People ask me, well what if they are NOT on a DOAC? My response is probably okay to omit the baseline anti-Xa level, but are you sure they are not on a DOAC? Is the medication reconciliation reliable? Thus, I’d rather over draw than under draw…….I view this very similar to daily INRs in the hospital which is clearly overkill most of the time, but standard practice at many facilities.
Finally, I’ve become a little concerned that many clinicians are not applying kinetics knowledge to anticoagulants (I say to our residents every day that kinetics are not just for gentamicin and vancomycin….); I can think of no more critical of a situations where you need to do this than these heparin transitions issues (and anticoagulation reversal concepts). Impossible for me to explain in a blog post, but think about the concentrations of the drugs you are dealing with on a graph (you don’t need levels to do this…..) and reason through the situation. If you need help, simple contact me.
So, I'd love discussion if you agree/disagree with this post, as obviously much of this is my opinions on this topic!
Macedo KA, Tatarian P, Eugenio KR. Influence of direct oral anticoagulants on anti-factor Xa measurements used for monitoring heparin. Ann Pharmacother. 2018; 52:154–9. https://journals.sagepub.com/doi/abs/10.1177/1060028017729481?journalCode=aopd" target="_blank">Link
Billoir, et. al. Anti-Xa Oral Anticoagulant Plasma Concentration Assay in Real Life: Rivaroxaban and Apixaban Quantification in Emergency with LMWH Calibrator. Ann Pharmacother. 2018; 52:154–9 https://journals.sagepub.com/doi/abs/10.1177/1060028018811657?journalCode=aopd" target="_blank">Link
Time to Monitor Direct Oral Anticoagulants (DOACs) in Anticoagulation Clinics
Posted by gulseth.michael on September 25, 2018 at 3:45 PM
by Shelby Rabenberg, Pharm D Student Pharmacist
Edited by Michael P. Gulseth, Pharm. D., BCPS, FASHP
The scope of anticoagulation therapy is slowly changing due to the emergence of direct oral anticoagulants (DOACs). DOACs eliminate several problems that are seen with warfarin including need for frequent INR monitoring, dietary considerations and pre-operative bridging. Even though routine anticoagulation effect monitoring of DOACs is deemed as unnecessary, there are still risks that must be considered and monitored. Extended monitoring and adherence efforts are warranted with DOACs given the new problems that they present, such as drug-drug interactions, renal and hepatic dosing considerations, body weight, age and adherence. This has prompted some anticoagulation management clinics to broaden their scope to include DOAC management in addition to warfarin management.
There have been two studies conducted that demonstrate adherence patterns with the use of DOACs, specifically dabigatran. The first study was conducted to describe the relationship between adherence, pharmacist care and overall outcomes of patients that were prescribed dabigatran at a VA health facility.1 This study evaluated whether dabigatran monitoring within the first months by a pharmacist would optimize adherence and stroke outcomes in patients with atrial fibrillation. A retrospective, preimplementation-postimplementation study that monitored adherence and outcomes in dabigatran patients that were managed by anticoagulation clinic pharmacists (ACC) or received usual care. The average medication possession ratio (MPR) across each group over three months was the primary endpoint. Acceptable adherence was defined as an MPR of > 80%. Secondary endpoints included bleeding, stroke and VTE. Overall, the ACC patients were more likely to have reached the primary endpoint compared to the usual care patients (25% vs 10% p=NS). The mean MPR values were 93.1% in the ACC group and 88.3% in the usual care group, but this was not statistically significant. In regards to the secondary outcomes, none of the three events occurred in either group. Overall, this study demonstrated that VA patients treated with dabigatran that were followed by an anticoagulation clinic pharmacist did not differ from dabigatran patients receiving usual care. The patients did not differ in regards to secondary outcome events.
The second study evaluated specific modifiable site-level factors that were associated with improved dabigatran adherence.2 This study was mixed with retrospective quantitative and cross-sectional qualitative data. The study involved 67 Veterans Health Administration sites that had twenty or more patients that filled dabigatran prescriptions between 2010 and 2012 for nonvalvular atrial fibrillation. A total of 47 pharmacists from 41 sites participated in the study. Specific practices performed at each site included pharmacist guided patient education, adverse event and adherence monitoring, and appropriate patient selection. The primary outcome of this study was adherence to dabigatran. This was measured as the proportion of days covered (PDC), which is a ratio of days supplied by prescription to follow-up duration. The goal PDC was at least 80%. The results of this study showed that the median adherence proportion of dabigatran patients was about 74% with an interquartile range of 66%-88%, indicating a wide variation in proportion of adherent patients. The adherence rates across sites varied by an odds ratio of 1.57. Appropriate patient selection was performed at 31 sites, while pharmacist guided education was done at 30 sites and pharmacist monitoring was done at 28 sites. Patient selection (RR, 1.14; 95% CI, 1.05-1.25) and pharmacist guided monitoring (RR, 1.25; 95% CI, 1.11–1.41) were associated with better patient adherence. Longer duration of monitoring and collaborating with the prescriber in caring for nonadherence patients were also associated with increased adherence. Overall, the results of this study demonstrate the importance pharmacist guided management of DOACs.
Taken together, these studies appear to DOAC patient who were monitored by anticoagulation pharmacists had better adherence. Many aspects that should go into the DOAC management much like what is done with warfarin patients. Certain aspects of the clinic visits should include evaluating the risk versus benefits of anticoagulation and determining whether the use of a DOAC is appropriate, obtaining and assessing relevant baseline lab values and weight, conducting medication reconciliations, assessing and evaluating drug-drug interactions, proving patient education regarding adherence, bleeding and other specific DOAC adverse effects. In order to produce a successful monitoring clinic, there should be nine essential domains to maintain high-quality monitoring. These domains include qualified personnel, supervision, care management and coordination, documentation, patient education, patient selection and assessment, laboratory monitoring, initiation of therapy and maintenance of therapy. Because of the increasing use of DOACs, clinicians practicing in anticoagulation clinics should consider incorporating DOAC management into their practice. Engaging patients in a shared decision-making process to identify the most appropriate anticoagulant and ensuring safe long-term management are essential for high-quality, patient-centered anticoagulant care.3,4
1. Lee PY, Han SY, Miyahara RK. Adherence and outcomes of patients treated with dabigatran: pharmacist-managed anticoagulation clinic versus usual care. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. Jul 1 2013;70(13):1154-1161.
2. Shore S, Ho PM, Lambert-Kerzner A, et al. Site-level variation in and practices associated with dabigatran adherence. Jama. Apr 14 2015;313(14):1443-1450.
3. Barnes GD, Kurtz B. Direct oral anticoagulants: unique properties and practical approaches to management. Heart. Oct 15 2016;102(20):1620-1626.
4. Mohammad I, Korkis B, Garwood CL. Incorporating Comprehensive Management of Direct Oral Anticoagulants into Anticoagulation Clinics. Pharmacotherapy. Oct 2017;37(10):1284-1297.
Should we use fixed dose PCC for the reversal of anticoagulation?
Posted by gulseth.michael on June 20, 2018 at 5:25 PM
By Darren R Kueter, Student Pharmacist
Edited by Michael P. Gulseth, Pharm. D., BCPS, FASHP
PCC (prothrombin complex concentrate) is a reversal agent that can be utilized in the event of acute major bleeding or the need for urgent surgery in patients that are taking vitamin K antagonists such as warfarin. PCC does have many advantages over FFP (fresh frozen plasma) for the reversal of bleeding events. These advantages include quicker reconstitution (no thawing needed), a smaller volume of product needed, and lack of need for blood group typing. One challenge that PCC presents to clinicians is that dosing is dependent on the patient’s pre-dose INR and the patient’s body weight when reversing warfarin, per the package labeling based on the phase III trials. (1) Due to this, calculating dosing of PCC is challenging in acute life-threatening situations. Thus, some clinicians have been investigating using fixed doses of PCC for all patients to make this process much less complicated and speed delivery of product. Some data does support fixed-dose PCC for the reversal of VKA associated bleeding, but the specific fixed dose of PCC, specific patient bleeding situations, the specific PCC product used and time to reversal differ from study to study which makes the results difficult compare.
Current FDA Approved Dosing (1) :
INR 2 to <4 = 25 units/kg (max of 2500 units)
INR 4 to 6 = 35 units/kg (max of 3500 units)
INR >6 50 units/kg (max of 5000 units)
Available Vial sizes:
Data to evaluate the effectiveness of fixed-dose PCC:
Abdoellakhan et al. Fixed Versus Variable Dosing of Prothrombin Complex Concentrate in Vitamin K Antagonist-Related Intracranial Hemorrhage: A Retrospective Analysis (2) :
Retrospective study using Cofact (Cofact is very similar to Kcentra (contains clotting factors 2, 7, 9 and 10 but does not contain proteins C and S like Kcentra))
• Looked at the successful achievement of an INR less than equal to 1.5 with a fixed vs variable dosing strategy for PCC in patients with ICH due to VKA therapy.
• The two treatment arms were fixed dose PCC with a dose of 1000 IU ( n=28 and variable dose PCC with a median dose of 1750 IU (n=25).
• 68% of the patients in the fixed dose treatment arm achieved an INR less than equal to 1.5, while 96% of the patients in the variable dose treatment arm achieved an INR less than equal to 1.5 (p=0.01).
Astrup et al. Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis (3) :
• Retrospective analysis using Kcentra at a fixed dose of 1500 IU.
• Looked at how many of the total of 37 patients achieved an INR less than equal to 1.5 after a single dose of 4FPCC (Kcentra) and how many of the patients achieved an INR less than equal to 2 after a single dose of 4FPCC (Kcentra).
• Two of the patient’s in this study had pre-treatment INRs of less than equal to 1.5 and were not included in the efficacy analysis. 74% (n=26) of patients achieved an INR less than equal to 1.5.
• Seven of the patient’s in this study had pre-treatment INRs of < 2 and were not included in the efficacy analysis. 100% (n=30) of patients achieved an INR < 2.
• No thrombotic events were reported within 7 days of the administration of 4FPCC (Kcentra) in these patients.
Klein et al. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal (4) :
• Retrospective study using Kcentra at a fixed dose of 1500 IU.
• Looked at how many of the total of 39 patients achieved an INR <2 and how many of them achieved an INR < 1.5 after reversal with 4FPCC.
• 92.3% (n=36) of patients reached the goal INR <2 after reversal with 4FPCC, and 71.8% ( n=28 of patients reached the goal INR <1.5 after reversal with 4FPCC.
• No thrombotic events were reported in the 7 days following reversal with 4FPCC (Kcentra) in these patients.
Khorsand et al. An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies (5) :
• Observational prospective study using Cofact to assess the non-inferiority of fixed-dose PCC (n=101) when compared to variable-dose PCC (n=139).
• Looked at the number of patients that reached an INR of < 2 after PCC treatment and the number of patients that reached a successful clinical outcome after PCC treatment.
• The fixed-dose group received 1040 UI F IX and the variable dose group received a median dose of 1560 UI F IX.
• 92% of the patients in the fixed-dose group reached an INR of <2, while 95% of the patients in the variable-dose group reached an INR of <2 after treatment with PCC. Risk difference -2.99% (90% CI -8.6 to 2.7). Fixed dose not found to be non-inferior.
• 96% of the patients in the fixed-dose group had a successful clinical outcome, while 88% of the variable-dose group had a successful clinical outcome. Risk difference 8.3% (90% CI 2.7 to 13.9). Fixed dose found to be non-inferior.
This data seems to suggest that fixed doses of PCC around 1500 units have a good mix of efficacy and safety while fully acknowledging this is not well-controlled data. Despite the relatively small amount of data available, the American College of Cardiology (ACC) has supported a fixed dose of PCC. (6) In their decision pathway for the management of bleeding in patients on oral anticoagulants, the ACC suggests administering 1000 units for any major bleed and 1500 units for intracranial hemorrhage. This sets up the following questions:
1. We are curious at what other facilities are doing out there. Are you using fixed doses?
2. If fixed dose is used, is it used for warfarin only or off-label for DOAC reversal?
3. Will the manufacturer create 1500 unit vial size? You would think this would be a market opportunity for them, but want to hear others thoughts.
Please comment below.
1. CSL Behring. Kcentra (Prothrombin Complex Concentrate, Human) prescribing information. www.kcentra.com/prescribing-information. Accessed May 23, 2018.
2. Abdoellakhan RA, Miah IP, Khorsand N, Meijer K, Jellema K. Fixed Versus Variable Dosing of Prothrombin Complex Concentrate in Vitamin K Antagonist-Related Intracranial Hemorrhage: A Retrospective Analysis. Neurocritical care. Feb 2017;26(1):64-69.
3. Astrup, G., Sarangarm, P. & Burnett, A. Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis. Journal of Thrombosis and Thrombolysis. 2018 45: 300.
4. Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. The American journal of emergency medicine. Sep 2015;33(9):1213-1218.
5. Khorsand N, Veeger NJ, van Hest RM, Ypma PF, Heidt J, Meijer K. An observational, prospective, two-cohort comparison of a fixed versus variable dosing strategy of prothrombin complex concentrate to counteract vitamin K antagonists in 240 bleeding emergencies. Haematologica. Oct 2012;97(10):1501-1506.
6. Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, et al. 2017 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants. Journal of the American College of Cardiology. Dec 2017; 1-26.
Andexanet Alpha Approval, Where to Begin?
Posted by gulseth.michael on May 10, 2018 at 10:00 AM
One thing I love about my job is it never gets boring…….
Unless you live under a rock, I am sure you are aware the first specific reversal agent for factor Xa inhibitors has been approved. The full package insert can be found at: https://www.andexxa.com/prescribing-information/
Now, as an antithrombotic pharmacist, I’ve been following the development of this agent very closely for years. Here is a list of issues I am immensely interested in:
1. Pricing. In my field, they are in a league of their own. I was thinking, based on other market agents, they’d price around $10,000 for low dose and $20,000 for high dose, but I was not even close. The exact price is about $27,500 per gram, so even low dose infusions (most apixaban for example) will be close to $25,000. (Note infusion length; see below.)
2. Data with the agent is remarkable that since it was a technological breakthrough, it has never been compared to no agent/placebo, or clotting factor agents like prothrombin complex concentrate (PCC). Further, while not high quality data, there is some data suggesting PCC is useful in life threatening Xa inhibitor bleeds.1 With that said and in fairness to andexanet, I get nervous raising physiologic levels of clotting factors to supra-physiologic levels which is what PCC does in these patients.
3. There is a potential concern that andexanet inhibits tissue pathway factor inhibitor potentially inducing a hypercoagulable state.2, 3 The agent has a boxed warning since thrombotic events were noted in the trial, but since there was not a comparator, it is impossible to know if this was normal disease course in patients inherently at risk of thromboembolism or an issue with the reversal agent.
4. The agent has a very short ½ life, much shorter than the agents it will be used to reverse. Is an infusion of a bit more than 2 hours (when bolus included) really enough time for every single patient? Note they have not done a surgical reversal trial. Also, the price is based on a 2 hour infusion after the bolus.
5. Is this the formal dawn where all facilities need rivaroxaban and apixaban calibrated anti-Xa levels? You can make a strong argument it could make sense to check the levels after stopping the infusion in some cases and using them to help guide care. (Not to mention they are better at directing initial care, too, than pt/INR too.)
6. Availability. Most will not be able to access this medication until at least 2019.
So, what do anticoagulation clinicians need to do in light of all of this?
1. Engage your pharmacy and hospital administration now. They need to understand and appreciate the potential financial ramifications of this agent. You have time to do this before it is available.
2. Engage critical medical staff groups, such as hospitalists, emergency department physicians, cardiologists, intensivists, pharmacists, neurologists, trauma surgeons, and neuro surgeons now, not after the drug is released. They need to know what we know, what we don’t know, and the price of therapy.
3. Update your reversal orders before this drug is released, and release them when it is. The dosing is complicated based on agent and timing, and errors are very likely. Further, take steps to assure clinicians follow the recent ACC/AHA consensus decision pathway on bleeding management. http://www.onlinejacc.org/content/early/2017/11/10/j.jacc.2017.09.1085?_ga=2.196811172.901783200.1525897874-344143112.1519406263
4. Do what is possible to educate and put in guidelines this should not be used immediately in most GI bleeds. They key point being the antidote could be worse than the poison in those situations.
5. For pharmacists, get yourself to the bedside as much as possible in these situations. You have a key role to play in helping guide individual care due to your knowledge of pharmacology and pharmacokinetics. I can think of no better way to show value to your organization, and document your activities.
Questions for discussion that I hope some of you will comment on:
1. Considering the data issues, price, and possible thrombotic risk, will any hospitals decide not to put this on formulary and simply use PCC?
2. What are you going to do specifically to limit use to only the patients who really need it?
3. How are you going to deal with the financial ramifications of potential length of the infusion creep?
4. Are any of you going to pursue setting up research based rivaroxaban and apixaban levels at your facility? We have them and are using them already in this population as an initial lab.
1. Schulman S, Gross PL, Ritchie B, et. al. Prothrombin complex concentrate for major bleeding on factor Xa Inhibitors: a prospective cohort study. Thromb Haemost. 2018 Mar 21. doi: 10.1055/s-0038-1636541. [Epub ahead of print]
2. Lu G, Lin J, Curnutte JT, Conley PB. Andexanet Alfa, a Universal Antidote Under Development for Factor Xa Inhibitors, Reverses Rivaroxaban-Induced Inhibition of Thrombin Generation Initiated By the Intrinsic Coagulation Pathway Independent of TFPI [poster]. American Society of Hematology 58th Annual Meeting. December 3-6, 2016; San Diego, CA. Abstract 3831.
3. Lu G, Lin J, Coffey G, Curnutte JT, Conley PB. Interaction of andexanet alfa, a universal antidote to fXA inhibitors, with tissue factor pathway inhibitor enhances reversal of fXA inhibitor-induced anticoagulation. Journal of thrombosis and haemostasis : JTH. 2015;13:634-635.
Michael P. Gulseth, Pharm. D., BCPS, FASHP
On Demand CE on Laboratory Issues with DOAC Therapy
Posted by gulseth.michael on April 29, 2017 at 12:40 AM
I recently partnered with Stago to create a new, on demand activity talking about contemporary laboratory issues with DOAC therapy. It is called "Direct Oral Anticoagulant Screening and Measurement for Challenging Patient Cases" and can be found at this link:
I do realize pharmacists cannot get CE for this, but other professionals can. With that said, these are critical issues to pharmacists working in anticoagulation, so hope you will still give it a listen.
After you have a chance to finish this, let me know what you thought in the comments below. I present numerous real world cases, so hoping this is helpful.
Michael P. Gulseth, Pharm. D., BCPS, FASHP
Bariatric surgery and DOACs; what to do?
Posted by gulseth.michael on April 25, 2017 at 2:20 PM
Soon after the advent of direct oral anticoagulation therapy, we were confronted with what should we do in patients with new or history of bariatric surgery. At our hospital, we quickly moved away from them in this population, but it is a deficient topic that in all of the DOAC package labels.
Thankfully, a recent, excellent review was pulblished on this topic:
Martin KA, Lee CR, Farrell TM, Moll S. Oral Anticoagulant Use After Bariatric Surgery: A Literature Review and Clinical Guidance. The American journal of medicine. May 2017;130(5):517-524.
I encourage all to read this, but here are the notations I took away from the article:
Changes to absorption of direct oral anticoagulants (DOACs, ie dabigatran etexilate [Pradaxa®], rivaroxaban [Xarelto®], apixaban [Eliquis®], and edoxaban [Savaysa®] likely affects the efficacy and safety of these medications in the bariatric surgery population.
The term “bariatric surgery” covers many different procedures such as adjustable gastric banding (AGB), sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and biliopancreatic diversion with duodenal switch (PBD-DS).1 Different procedures likely have varying degrees of impact on DOAC efficacy and safety.
Bariatric surgery is theorized to potentially having the following effects on DOACs:
o Reduction of rivaroxaban absorption since it requires food for optimal absorption.
o Reduction in gastric acid production raising pH. Dabigatran is known to require an acidic environment for effective absorption.
o Motility may be increased leading to inadequate absorption.
o Surgeries that bypass the small intestine may alter enteric metabolism and efflux/influx of drugs across the intestinal wall.
o Disruption of drug absorption:
Apixaban is absorbed in the proximal small intestine, in addition to a little stomach absorption and colonic absorption.
Rivaroxaban is likely absorbed primarily in the stomach, with less absorption in the proximal small intestine.
Dabigatran is likely absorbed in lower stomach and proximal small intestine.
Edoxaban is mainly absorbed in the proximal small intestine
Patients who require bariatric surgery likely have much higher volumes of drug distribution than standard patients, and the volume of distribution can fluctuate as weight loss occurs. Some of the agents likely due distribute into the fats.
Although warfarin also relies heavily on gastric and proximal intestinal absorption, the dose can typically be customized to overcome any absorption issues by titrating to target INR, while the same is not true of DOAC agents since optimal target values are not known, and the difficulty in titration/laboratory testing.
My recommendations (which are very simiar to the article):
1. Clinicians should utilize warfarin therapy as the first line agent for patients who required systemic anticoagulation with a history of bariatric surgery. Further, patients on DOACs who have bariatric surgery should be converted to warfarin therapy in most cases.
2. If there is a compelling reason to utilize a DOAC over warfarin, I suggest considering the type of surgical procedure and pick an agent less likely to have absorption affected. (Apixaban appears to me to have the most optimal profile in that regard, but this is educated speculation on my part.) Further, I would suggest checking peak and trough levels to see if they are within the expected values. (If research drug levels are not available, could traditional labs be used? Difficult quesiton to answer. See http://members.webs.com/MembersB/editAppPage.jsp?app=blog&pageID=352382419#blog/show/44500337-doac-effects-on-traditional-labs)
Agree, disagree with my conclusions? Please comment below.
DOAC effects on traditional labs
Posted by gulseth.michael on April 25, 2017 at 12:25 AM
I keep running into a lack of understanding of the effects of DOACs on traditional labs. I want to summarize, and keep this simple:
Dabigatran will modestly prolong aPTT at therapeutic and high levels. If normal, patient could still have therapeutic levels. Best lab to confirm low dabigatran levels for many is thrombin time. If the thrombin time is measurable or normal, patient likely has very low dabigatran levels.
Rivaroxaban typically causes a significant prolongation of pt/INR; degree of this will vary based on reagent. A normal pt/INR likely confirms low levels of rivaroxaban. If you work at a hospital using anti-Xa heparin levels, a measureable heparin level also likely indicates low levels of rivaroxaban.
Apixaban typically causes a prolongation of pt/INR; but not as much as rivaroxaban. A normal pt/INR likely confirms low levels of apixaban.
So, there it is in a nutshell. Current practice gaps/errors I see:
1. People giving vitamin K for high INRs due to rivaroxaban/apixaban to “reverse” them. I chuckle a little every time I see this.
2. Not recognizing the value of drawing labs to guide therapy in reversal, procedural situations, and guiding agent transitions. We need to step up and educate our colleagues on these issues.
As always, thank you for the great care you provide your patients.
Michael P. Gulseth, Pharm. D., BCPS, FASHP
Heparin Induced Thrombocytopenia (HIT) Care Issues
Posted by gulseth.michael on March 16, 2017 at 7:00 AM
HIT; it is the anticoagulation topic that you must know if you practice in hospitals in anticoagulation. I never cease to be amazed by the errors and mistakes that can happen when caring for HIT patients. I just want to pass along a few tips based on practical experience:
1. PF4 antibody testing is great if you remember it is very sensitive, but not very specific. Why? It tests for antibodies that bind to heparin/PF4 complexes. So, if the test is negative, you likely don't have antibodies capable of the disease. (remember the pathophysiology) It can serve as a pretty good rule out, but if indeterminant of positive, it can be challenging to interpret. Why? Because the test does not tell you if those antibodies are pathogenic. Thus, it is very important to consider the entire clinical picture. HIT is a clinical diagnosis and serotonin release assay testing can be helpful if you still have doubts on the diagnosis since it tests if the antibodies are pathogenic.
2. We still don't have data on the direct oral anticoagulants (DOACs) in HIT. I hope that day is coming as it will simplify care if they are successful.
3. I see a lot of errors in argatroban administration whenever I order it. It is a drug many are unfamiliar with, and dosing is in mcg/kg/min. I can't stress enough the importance of nurses and pharmacists working together to make sure the administration is right. And pharmacists, get out of your chair, and go physically check the pump and make sure it is right! Encourage nurses to program the actual dose into the smart pump, not the ml/hr rate.
4. If you set up an argatroban titration scale similar to a heparin titration scale, it is important to rewrite the titration parameters if there are big changes in the amount of argatroban being used. For example, if you start at 2 mcg/kg/min, and start stabilizing around 0.5 mcg/kg/min, you probably want to make smaller dose titrations on a mcg/kg/min basis based on aptt than you would have when on 2 mcg/kg/min.
What other tips do you have for caring for HIT patients? Please comment below.
Michael P Gulseth, Pharm. D., FASHP
Monday Morning Patient Care Thoughts
Posted by gulseth.michael on March 13, 2017 at 11:50 AM
While waiting for a doctor to call back so I can stop an un-needed heparin drip, I felt like writing a few miscellaneous thoughts on my mind:
1. We had another rivaroxaban to heparin transition yesterday. In this case, patient had acute PE and went into AKI while on rivaroxaban. 36 hours after a last dose of rivaroxaban, they drew a rivaroxaban level. It was 201 ng/ml, likely at a therapeutic level. Patient had a chest tube placed at that time (the reason rivaroxaban was held), and the question came to me if we wait to start a heparin drip. (We no longer felt rivaroxaban appropriate with AKI.) My answer was, yes, in this case probably better to error on the side of potential over anticoagulation. However, this is a case you have to use aptt to monitor heparin, so we customized a scale and are using that for now. I will wait two days, then maybe check an Xa level to see if in range or low. If it is, we can probably switch back to it at that time since our aptt goals have not been formally correlated to anti-Xa levels as they should be. See my previous blog if you are not aware of these transition issues.
2. A rookie mistake I often see in dosing warfarin for inpatients is a lack of appreciation for how much continuous tube feedings can increase warfarin needs. Don't be shy; get that dose increased!
3. I am convinced one of the biggest benefits our inpatient anticoagulation service provides is creating smooth transitions of care. It is worth the time we spend making sure all critical issues are addressed, and educating patients.
4. My life was simpler when we did not need to use Bactrim to treat MRSA.
5. Will winter ever end? This is starting to feel like a Game of Thrones kind of winter.
Michael P Gulseth, Pharm. D., BCPS, FASHP
Musings on Anti-Xa Activity Levels
Posted by gulseth.michael on March 8, 2017 at 1:30 PM
Recently, there was a good article in AJHP on dealing with transitions from oral Xa inhibitors to heparin. You can read it at AJHP 2016; 73:2037-41
This has piqued a lot of my interest in this subject since we actively use novel drug levels like dabigatran, rivaroxaban, and apixaban levels. We have published on this in the past. See: http://www.ajhp.org/content/early/2017/02/21/ajhp160168
Recently, I have been seeing a lack of understanding on how to handle these situations, so I want to offer some off the top of my head observations that are important for anticoagulation pharmacists and other clinicians managing anticoagulation to understand:
1. Heparin, enoxaparin, apixaban, and rivaroxaban levels are all exactly the same test. You add a known amount of factor Xa to plasma. The drug in the plasma then neutralizes a portion of that Xa. The free active Xa is detected by addition of a chromogenic substrate that emits color (optical density) (the higher the OD, the lower the concentration of the drug). The key concept is that the assay mechanism is the same no matter the Xa inhibiting drug you are evaluating.
2. So, why different results depending on the test you order? The test you order determines the coagulation analyzer test setup and the concentration curve on which you plot the OD. The OD makes no distinction regardless of the anti-Xa based drug in the sample.
Why am I bringing this up? I am seeing instances where patients are on a Xa inhibitor, and switches to heparin. Then, at the first Xa level, they are checking a heparin and Xa inhibitor level. This makes no sense; it is exactly the same OD reading. Both drugs affect the OD and you will have no way of determining which is affecting which. One would expect the oral direct anti-Xa drug to affect the OD to a greater extent in this situation due to heparin bolus doses not usually pushing the anti-Xa level > 0.7. With that said, there are better options to manage this. For example, if you aren't worried about over anticoagulation, just check aPTTs until the Xa inhibitor has cleared as suggested in the first article above. If not an active thrombosis, or impaired clearance of the Xa inhibitor is likely, perhaps it is better to delay heparin until and apixaban or rivaroxaban level has dropped substantially, or you have seen prothrombins/INRs fall to levels closer to normal. Yes, I know these levels are not clearly defined.
Example, yesterday we had a patient come in on therapeutic rivaroxaban with an MI. I was called if okay to bolus heparin and put on a drip. My response was yes, considering it was an active thrombotic state, risking over anticoagulation is justified since the rivaroxaban did not prevent the MI. So, in that case, we used aPTT to monitor the heparin, since rivaroxaban has little effect on that test.
In different case a few weeks ago, a patient came in on apixaban 2.5 mg bid. Patient had CKD and new AKI. Apixaban initially continued until a coag pharmacist recognized this was inappropriate. Package insert for converting to heparin was used, but heparin levels sky high, assuredly from the apixaban not clearing. So, after I knew the heparin would be gone after stopped (ie 6 hours), I used apixaban levels to help determine when we could restart heparin since there was no active thrombosis and this was merely a bridging situation.
I realize anticoagulation is getting more complicated, but I can’t think of a better way to demonstrate value to the patient care team then helping in these complicated situations. As always, I am here to help; please comment below.
Michael P Gulseth, Pharm. D., BCPS, FASHP
2017 ISMP Antithrombotic Therapy Self-Assessment
Posted by gulseth.michael on February 17, 2017 at 11:30 AM
Excited to announce the realease of the new, 2017 ISMP Medication Safety Self-Assessment for Antithrombotic Therapy. I would strongly encourage all practitioners who work in health-systems to review these new guidelines so we can keep our patients safe. They do cover direct acting oral anticoagulants.
Thank you, as always, to the leadershp shown by ISMP!
Michael P. Gusleth, Pharm. D., BCPS, FASHP