Recommendation for the Reversal of Novel Anticoagulants in Emergent Situations

Transcription

1 Lauren Edwards PharmD Candidate 2016 Truman Medical Center, Lakewood Preceptor: Dr. Melissa Gabriel June 11, 2015 Recommendation for the Reversal of Novel Anticoagulants in Emergent Situations Background Within the last several years, new anticoagulant medications have been used to treat patients with thromboembolic disorders and risk factors for an adverse bleeding event. These agents are preferred by many physicians because of their minimal food and drug interactions; thereby requiring less frequent monitoring and dosing fluctuations in comparison to Warfarin (Coumadin) [1]. Dabigatran (Pradaxa) is a direct thrombin inhibitor that can be taken orally. By acting directly on thrombin, it can prevent clot development with either clot-bound thrombin or thrombin-induced platelet aggregation [2]. There is no recommended dosing regimen in patients with a creatinine clearance less than 30 ml/minute or in dialysis patients, and no other monitoring parameters need to be measured with this medication. Rivaroxaban (Xarelto) and Apixiban (Eliquis) are direct factor Xa inhibitors. These agents are becoming increasingly more popular in prophylaxis of patients undergoing major orthopedic surgery (especially hip and knee) [3]. Both agents have to be used cautiously in low kidney function as well as with other agents that act on similar receptors [2] but require no additional monitoring. According to the 2012 CHEST guidelines, these new anticoagulants should be anticipated to be used for an extended period of time. In patients with a provoked venous thromboembolic episode, these agents can be used for up to three months, and in an

2 unprovoked incident the length is extended. If a second episode occurs, regardless of the source, anticoagulants will in all probability be used for life [3]. With older agents such as Warfarin (Coumadin) and Enoxaparin (Lovenox), a reversal agent can be used in emergency cases where there is a major bleed. Because of the novelty of the factor Xa and direct thrombin inhibitors, no reversal agent has been developed and approved. There are currently three agents in clinical development that are designed to reverse these anticlotting agents, but it could take many years before they are available for use. Idarucizumab is a fragmented antibody that is being investigated to reverse dabigatran (Pradaxa); adexanet alfa is designed to bind to and reverse the anticoagulant properties of factor Xa; and aripazine is an artificial agent that was created to reverse all novel anticoagulants as well as fondaparinux and low molecular weight heparin [4]. [4] [4]

3 Study Analysis It is challenging to find suitable agents for reversing specific situations because of the limited amount of data and studies performed. Many of these studies examined use in animals, ex-vivo, or in-vivo in healthy volunteers. This makes it impossible to know how these reversal agents would work in a human patient with an active bleed. The tests looking at human data also employ coagulation tests, which reflect outcomes that cannot represent efficacy in the context of bleeding [5]. A recent study conducted at the Academic Medical Center in Amsterdam, the Netherlands looked at 12 healthy male subjects. They were randomized in a double-blind, placebo-controlled, crossover trial. The participants received a standard dose of either rivaroxaban or dabigatran for three days before being admitted to the hospital to be infused with either PCC (Cofact) or a saline placebo. A blood sample was collected 24 hours after this infusion. After a washout period of 11 days, the participants switched to the other anticoagulant medication for three days, and were given PCC (Cofact) or a saline infusion in the hospital on the third day of treatment. A second blood sample was collected 24 hours after this infusion. The study analyzed coagulation tests to measure prothrombin time (PT), endogenous thrombin potential (ETP), and activated partial thromboplastin time (aptt). A paired t test was used to determine statistical significance with ANOVA to validate the results. It was found that nonactivated PCC (Cofact) immediately reversed the effects of full-dose rivaroxaban but did not have any effect on dabigatran. However, there are many limitations with this study that need further examination. One limitation is the small sample population, creating a lack of external validity. The study looked at twelve healthy volunteers. The findings in this group cannot be accurately applied to the typical treatment population. Many hospitalized patients have impaired

4 renal function and may also have conditions that could hinder or affect the use of PCC for reversal of these agents. Another limitation is that a single standard dose of PCC was given to patients. At the conclusion of the study, results from the ETP showed an increase over time that could potentially be caused by a surplus generation of thrombin in the blood. Because of this, a smaller dose of PCC could be more beneficial in the reversal of rivaroxaban. This also could be why dabigatran appeared to be unaffected by the PCC given. If a higher dose of PCC was given to patients receiving dabigatran, there is the possibility that this could have reversed the anticoagulant effects. The other limitation of administering one dose of PCC is that it does not show if dabigatran and rivaroxaban have the potential to be reversed by alternative strategies, such as using repeated PCC administration, administering an adjunct agent such as recombinant factor VIIa, or by using recombinant factor VIIa by itself. By taking measurements between 6 and 24 hours after receipt of the PCC or placebo, the study does not take into consideration if any reversal of rivaroxaban and dabigatran was achieved in the first minutes or hours after administration. Additionally, any effects PCC may have had after the 24 hour window would not be observed [1]. Another recent study conducted in Linkoping, Sweden looked at blood samples of twenty healthy men and women. The samples were collected and then randomized. Dabigatran was dissolved in DMSO and added to the citrated blood in a standard concentration of 200 ug/l. A reversal agent was added in the smallest allowable volume to the tubes and normal saline was used as the placebo for the control tubes. The reversal agents examined for the tests were recombinant activated factor VII, activated prothrombin complex concentrate (FEIBA), and prothrombin complex concentrate (Cofact). The study showed that APCC significantly shortened clotting time in the samples but PCC had no effect. It was also observed that the

5 rfviia shortened the clotting time, but the results were not significant. One large limitation of this study was that it was conducted using only samples, so any regulatory mechanisms would not be affected by the results; thus making them less likely to be able to be applied to the population as a whole [6]. Prior to both studies, an investigation of bleeding in a rat s tail was conducted using Feiba (activated PCC). This showed that Feiba had no influence on a prolonged aptt, but did reverse the bleeding time produced by dabigatran. However, these results are surrogate markers in bleeding and do not accurately capture an active bleeding event in a human [1]. Clinical Recommendations from other Institutions Eric Liotta, a member of the Department of Neurology and Department of Pharmacology of the Feinberg School of Medicine at Northwestern University, wrote a review summarizing the available data for novel anticoagulant reversal in Although the agents undergoing clinical trial are not available at this time, the recommendation from Northwestern University is to use activated or unactivated 4-factor PCCs to reverse any of the novel anticoagulants. He recommended that institutions add this to their formulary until the new agents are available [7]. Physicians at Yale University also looked at the available data to help determine a protocol for reversal of novel anticoagulants. For reversal of dabigatran, they write: Our approach at present is to recommend drawing pretreatment laboratory tests (PT/INR, PTT, TT, and a complete blood count) and, in the event of an overdose within the past 2 hours, the administration of activated charcoal. If the patient has mild bleeding (defined as World Health Organization [WHO]

6 grade 1 2), we recommend supportive care and careful observation. If the patient has life-threatening bleeding (WHO grade 3 4), we recommend hemodialysis if (1) the patient's creatinine clearance is below 30 ml/min, (2) the patient has acute kidney injury, and (3) the last dose of dabigatran was more than 2 but less than 12 hours before presentation. If criteria for hemodialysis are not met, we recommend delaying/discontinuing dabigatran, fluid support (including blood product support) as needed, and the consideration of off-label use of 4-factor PCC (25 units/kg, dose not to exceed 2500 units). We do not recommend redosing the 4-factor PCC, nor do we recommend providing rfviia or FEIBA within 24 hours of a dose of the 4-factor PCC owing to our concern for possible thromboembolic complications. [8] When discussing their recommendations for reversal of rivaroxaban and apixaban, they state: As with dabigatran reversal, we always recommend drawing pretreatment laboratory tests (PT/INR, PTT, and a complete blood count) and, in the event of an overdose within the past 2 hours, the administration of activated charcoal. If the patient has mild bleeding (defined as WHO grade 1 2), we recommend

7 supportive care and careful observation. If the patient has life-threatening bleeding (WHO grade 3 4), we recommend delaying/discontinuing the drug in question, fluid support (including blood product support) as needed, and the consideration of off-label use of a one-time dose of the 4-factor PCC (25 units/kg, dose not to exceed 2500 units). As with dabigatran reversal, we do not recommend redosing the 4-factor PCC, nor do we recommend providing rfviia or FEIBA within 24 hours of a dose of the 4-factor PCC [8]. Doctors at the University of Pennsylvania and McMaster University compiled a flowchart suggesting management of a major bleed in patients that are taking novel oral anticoagulants [9]. [9]

8 The team suggested that non-specific pro-hemostatic agents (apcc) be given to patients with a major, life-threatening bleed even with the limited evidence available. It has been shown that apcc is preferred over 4-PCC in the available data for patients on dabigatran and that patients on rivaroxaban, apixaban, or edoxaban will benefit more from 4-PCC than apcc. Adjunctive therapies can also be used in patients for acute reversal. Hemodialysis can reduce dabigatran levels if there is bleeding caused by the medication or if the patient has renal dysfunction. It has been shown that 68% of the active dabigatran was removed after 4 hours of ingestion in patients with end-stage renal disease. Activated charcoal can also be used in patients for acute reversal of dabigatran, but there are no recommendations for patients on the other agents. The team also recommended using fresh frozen plasma only in situations where patients do not have an abundance of coagulation factor [9]. Final Recommendation Summary Based upon the clinical data and recommendations from several medical centers, I suggest that Truman Medical Center, Lakewood consider using apcc to reverse dabigatran (Pradaxa) in an emergent medical situation. If a patient recently ingested the medication, hemodialysis can be used to decrease its clinical effects. While the suggestions for reversal of dabigatran vary between using apcc and 4-PCC, it seems that apcc would be the safest and most efficacious option. I would consider using a protocol similar to the University of Pennsylvania, using 80 IU/kg in the event of a severe bleed based upon WHO criteria [9]. The evidence for reversal of the factor Xa inhibitors universally suggests 4-PCC as the best agent. I would also recommend utilizing the protocol implemented by Yale University (see

9 above) to determine when to use the reversal agent and what steps to take if an adverse bleeding event occurs while on these types of medications. While there is not a preponderance of strong evidence surrounding reversal of novel anticoagulants, there is promise for future development of agents that will work specifically to reverse these medications. Until these agents are approved for use in patients, it is important to utilize the best possible alternative in these emergent situations. References [1] Eerenberg E, Kamphuisen P, Sijpkens M, et al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate. American Heart Association. 2011; 124: doi: /CIRCULATIONAHA [2] Apixaban, Rivaroxaban, Dabigatran. Drug Reference Mechanism of Action. [updated 2015; cited 2015 June 11]. In: Micromedex Drug Reference Application for iphone. Ann Arbor, MI: Truven Health Analytics. C2015. [3] American College of CHEST Physicians Resources/Guidelines-and-Consensus-Statements/Antithrombotic-Guidelines-9th-EdCHEST guidelines [4] Yoonsun M, Yam F. Recent Advances in the Development of Specific Antidotes for Target- Specific Oral Anticoagulants. Pharmacotherapy. 2015; 25(2): doi: /phar [5] Siegal, D. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. Thrombosis Research. 2015: 39: doi: /s

10 [6] Lindahl T, Wallstedt M, Gustafsson K, et al. More efficient reversal of dabigatran inhibition of coagulation by activated prothrombin complex concentrate or recombinant factor VIIa than by four-factor prothrombin complex concentrate. Thrombosis Research. 2015; 135: doi: /j.thromres [7] Liotta E, Levasseur-Franklin K, Naidech A. Reversal of the novel oral anticoagulants dabigatran, rivoraxaban, and apixaban. Current Opinion Critical Care. 2015; 21: doi: /MCC [8] Gehrie E, Tormey C. Novel Oral Anticoagulants: Efficacy, Laboratory Measurement, and Approaches to Emergent Reversal. Archives of Pathology and Laboratory Medicine. 2015; 139(5): doi: [9] Siegal D, Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. Thrombosis Research. 2013; 35: doi: /s