Reversal Of Oral Anticoagulants Research Articles

Emergent Reversal of Oral Anticoagulation

Emergent Reversal of Oral Anticoagulation

The Use of Prothrombin Complex Concentrates in Two Patients With Non-Pulsatile Left Ventricular Assist Devices

LEFT VENTRICULAR ASSIST DEVICES (LVADs) are becoming more prevalent in the treatment of heart failure. Nonpulsatile LVADs require long-term anticoagulation to prevent device thrombosis. Life-threatening bleeding or the need for urgent noncardiac surgery may necessitate reversal of this anticoagulation. The authors describe 2 cases of successful reversal of oral anticoagulation with prothrombin complex concentrates (PCCs) in patients with LVADs undergoing urgent noncardiac surgery, without evidence of device thrombosis.

New oral anticoagulant drugs: real-world data.

Oral anticoagulants or ‘blood thinners’ were proposed in 400 BC during the time of Hippocrates [1]. The first paper entitled ‘Coumadin (warfarin) sodium – a new anticoagulant’ was published in 1956 [2]. Despite its limitations, coumadin stood the test of time. Ximelagatran, a very potent oral thrombin inhibitor, licensed in Europe for a short time, was later withdrawn in 2006 for concerns of causing hepatotoxicity [3].

Current State of Knowledge on Oral Anticoagulant Reversal Using Procoagulant Factors

To discuss current trends and challenges in the use of procoagulants for treating bleeding caused by use of oral anticoagulants. Literature searches of PubMed (MEDLINE), Google, and Medscape were conducted in February 2013. There were no date limitations. Search terms included anticoagulation agents, anticoagulation reversal, anticoagulation reversal agents, apixaban, clinical studies, dabigatran, 3-factor PCCs, 4-factor PCCs, FEIBA, fresh frozen plasma, human studies, pharmacology, prescribing information, rFVIIa, rivaroxaban, vitamin K, and warfarin. Warfarin has been the mainstay for the treatment and prevention of primary and secondary thrombosis in patients with cardiovascular dis orders such as atrial fibrillation, deep vein thrombosis, pulmonary embolism, and stroke. Three oral anticoagulants have recently become available in the US: a direct thrombin inhibitor, dabigatran etexilate, and 2 direct factor Xa inhibitors, rivaroxaban and apixaban. Reversal strategies for anticoagulant-associated bleeding are well established for warfarin; however, strategies to stop bleeding in a patient who has taken one of the newer anticoagulants are less clear. In the US, agents available for oral anticoagulant reversal include activated prothrombin complex concentrate (APCC), 3-factor PCCs, and recombinant activated factor VII (rFVIIa). Few studies have evaluated the 3-factor PCCs, and current evidence for APCC and rFVIIa as reversal agents for dabigatran and rivaroxaban is based primarily on laboratory or animal studies, or on small studies in healthy humans and case reports. Patients contemplating using the new oral anticoagulants should be informed about specific clinical situations that could pose a bleeding risk such as the need for emergency surgery because no reliable antidote is available to stop the bleeding, which could prove fatal.

Pharmacologic interventions for reversing the effects of oral anticoagulants

To describe the pharmacologic agents and strategies used for urgent reversal of warfarin and the target-specific oral anticoagulants dabigatran, rivaroxaban, and apixaban. To reverse the anticoagulant effects of warfarin in patients who are bleeding or need surgery, exogenous vitamin K (phytonadione) may be used in combination with another, shorter-acting intervention, such as fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), recombinant factor VIIa, or activated PCC (aPCC). Three-factor PCC contains factors II, IX, and X in an inactivated form, and four-factor PCC also includes factor VII in an inactivated form. No four-factor PCC products are available in the United States, but aPCC, which contains the same four factors with factor VII provided in an activated form, is available. The intervention depends on the International Normalized Ratio, presence of bleeding, and need for and timing of surgery. Research suggests that clotting factor concentrates are more effective than FFP alone for warfarin reversal. These products also may be useful for reversing the effects of target-specific oral anticoagulants, but limited efficacy and safety data are available to support their use. The risks and benefits associated with these products need to be weighed before their use for reversal of dabigatran, rivaroxaban, or apixaban. Additional clinical data are needed to clearly define the role of concentrated clotting factor products in reversal and to determine the optimal clotting factor concentrate product and dose for urgent reversal of oral anticoagulation. Phytonadione and clotting factor concentrates appear to have a role for reversal of warfarin, and limited evidence suggests that clotting factor concentrates could have a role in reversal of target-specific oral anticoagulants in an emergency situation.

Developing a management plan for oral anticoagulant reversal

To describe a process for prompt evaluation and management- including reversal of the effects of warfarin and target-specific oral anticoagulants-of patients with or at high risk for bleeding during oral anticoagulant therapy or when such therapy is interrupted for an urgent invasive procedure or surgery. The use of pharmacologic interventions for anticoagulant reversal may depend on the measured level of anticoagulation, time since the last anticoagulant dose, target level of coagulation, reliability of laboratory tests of coagulation, severity of or risk for bleeding, the agents' mechanism of action and pharmacokinetics, and pharmacodynamics of the reversal agent. The patient's age, weight, renal function, comorbid conditions, and other drug therapy, as well as the risk for thromboembolism and other adverse effects of the reversal therapies, also enter into therapeutic decisions. Hemodialysis may be used to remove the direct thrombin (factor IIa) inhibitor dabigatran and reverse its anticoagulant effects. Limited experience with clotting factor concentrates suggests that activated prothrombin complex concentrate may be useful for reversing the anticoagulant effects of dabigatran. The activity of oral factor Xa inhibitors (i.e., rivaroxaban and apixaban) is higher up the common pathway of the coagulation cascade and thus may be easier to reverse than that of direct thrombin inhibitors. Additional clinical experience is needed to identify the optimal reversal agents, dosage, and impact on thrombosis or bleeding outcomes for both classes of agents. A comprehensive plan individualized to each agent should be developed to promptly reverse the effects of oral anticoagulants and optimize outcomes in patients with bleeding or an urgent need for surgery.

Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study

BackgroundThe rapid reversal of the effects of vitamin K antagonists is often required in cases of emergency surgery and life-threatening bleeding, or during bleeding associated with high morbidity and mortality such as intracranial haemorrhage. Increasingly, four-factor prothrombin complex concentrates (PCCs) containing high and well-balanced concentrations of vitamin K-dependent coagulation factors are recommended for emergency oral anticoagulation reversal. Both the safety and efficacy of such products are currently in focus, and their administration is now expanding into the critical care setting for the treatment of life-threatening bleeding and coagulopathy resulting either perioperatively or in cases of acute trauma.MethodsAfter 15 yr of clinical use, findings of a pharmacovigilance report (February 1996–March 2012) relating to the four-factor PCC Beriplex P/N (CSL Behring, Marburg, Germany) were analysed and are presented here. Furthermore, a review of the literature with regard to the efficacy and safety of four-factor PCCs was performed.ResultsSince receiving marketing authorization (February 21, 1996), ∼647 250 standard applications of Beriplex P/N have taken place. During this time, 21 thromboembolic events judged to be possibly related to Beriplex P/N administration have been reported, while no incidences of viral transmission or heparin-induced thrombocytopenia were documented. The low risk of thromboembolic events reported during the observation period (one in ∼31 000) is in line with the incidence observed with other four-factor PCCs.ConclusionsIn general, four-factor PCCs have proven to be well tolerated and highly effective in the rapid reversal of vitamin K antagonists.

Reversal of Oral Anticoagulation

Although the use of dabigatran and rivaroxaban are increasing, data on the reversal of their effects are limited. The lack of reliable monitoring methods and specific reversal agents renders treatment strategies empirical, and as a result, treatment consists mainly of supportive measures. Therefore, we performed a systematic search of the PubMed database to find studies and reviews pertaining to oral anticoagulation reversal strategies. This review discusses current anticoagulation reversal recommendations for the oral anticoagulants warfarin, dabigatran, and rivaroxaban for patients at a heightened risk of bleeding, actively bleeding, or those in need of preprocedural anticoagulation reversal. We highlight the literature that shaped these recommendations and provide directions for future research to address knowledge gaps. Although reliable recommendations are available for anticoagulation reversal in patients treated with warfarin, guidance on the reversal of dabigatran and rivaroxaban is varied and equivocal. Given the increasing use of the newer agents, focused research is needed to identify effective reversal strategies and develop and implement an accurate method (assay) to guide reversal of the newer agents. Determining patient-specific factors that influence the effectiveness of reversal treatments and comparing the effectiveness of various treatment strategies are pertinent areas for future anticoagulation reversal research.

Reversal of novel oral anticoagulants in patients with major bleeding

Novel oral anticoagulants (NOACs) that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban) are effective therapies for the prevention and treatment of thromboembolism with reduced bleeding complications compared with warfarin for some indications. However, specific antidotes to reverse the anticoagulant activity of NOACs in the event of major bleeding are not available. Evidence supporting non-specific prohemostatic therapies (prothrombin complex concentrate [PCC], activated prothrombin complex concentrate [aPCC], recombinant factor VIIa) in this setting is limited to healthy human volunteers, animal models, and in vitro studies. Clinical outcome data are lacking. Administration of PCC or aPCC may be considered in addition to supportive measures for patients with severe or life-threatening bleeding. Clinical studies are needed to establish the efficacy and safety of these treatments. Target-specific antidotes are in development and hold promise for NOAC reversal, but require further investigation.

Transitions of Care in Anticoagulation Management for Patients with Atrial Fibrillation

Thromboprophylaxis with oral anticoagulants (OACs) is an important but under-used element of atrial fibrillation (AF) treatment. Reduction of stroke risk with anticoagulants comes at the price of increased bleeding risk. Patients with AF receiving anticoagulants require heightened attention with transition from one care setting to another. Patients presenting for emergency care of anticoagulant-related bleeding should be triaged for the severity and source of the bleeding using appropriate measures, such as discontinuing the OAC, administering vitamin K, when appropriate, to reverse warfarin-induced bleeding, or administering clotting factors for emergent bleeding. Reversal of OACs in patients admitted to the hospital for surgery can be managed similarly to patients with bleeding, depending on the urgency of the surgical procedure. Patients with AF who are admitted for conditions unrelated to AF should be assessed for adequacy of stroke risk prophylaxis and bleeding risk. Newly diagnosed AF should be treated in nearly all patients with either warfarin or a newer anticoagulant. Patient education is critically important with all anticoagulants. Close adherence to the prescribed regimen, regular international normalized ratio testing for warfarin, and understanding the stroke risk conferred by both AF and aging are goals for all patients receiving OACs. Detailed handoff from the hospitalist to the patient's primary care physician is required for good continuity of care. Monitoring by an anticoagulation clinic is the best arrangement for most patients. The elderly, or particularly frail or debilitated patients who are transferring to long-term care, need a detailed transfer of information between settings, education for the patient and family, and medication reconciliation. Communication and coordination of care among outpatient, emergency, inpatient, and long-term care settings are vital for patients with AF who are receiving anticoagulants to balance stroke prevention and bleeding risk.

Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate

Both established oral anticoagulants such as warfarin and newer agents such as dabigatran etexilate (DE) effectively prevent thromboembolic disease, but may provoke bleeding. Limited clinical data exist linking oral anticoagulant reversal and bleeding tendency, as opposed to surrogate laboratory markers. To quantify bleeding in warfarin-anticoagulated and DE-anticoagulated mice by tail transection with or without pretreatment with potential reversal agents: prothrombin complex concentrate (PCC); activated PCC (APCC); recombinant factor VIIa (rFVIIa); or murine fresh-frozen plasma (FFP). CD1 mice were given warfarin or DE by gavage, and the effects on in vitro coagulation assays, volume of blood loss and the bleeding time following tail transection injury were evaluated with different reversal agents. PCC (14.3 IU kg(-1) ), but not rFVIIa (3 mg kg(-1) ) or FFP (12 mL kg(-1) ), normalized blood loss and bleeding time in mice with warfarin-induced elevations of mean prothrombin time at two intensities (prothrombin time ratios of either 4.3 or 24). Neither separate nor combined PCC and/or rFVIIa treatment nor APCC (100 U kg(-1) ) treatment significantly reduced blood loss in mice anticoagulated with 60 mg kg(-1) DE 75 min prior to tail transection. Both combined PCC plus rFVIIa treatment and APCC treatment significantly reduced bleeding time in the DE-treated mice. Our data suggest that PCC treatment prevents excess bleeding much more effectively in warfarin-induced coagulopathy than in DE-induced coagulopathy.

Treatment of bleeding after kidney biopsy with recombinant activated factor VII

Recombinant activated factor VII (rFVIIa) is approved for prevention and treatment of bleeding in hemophilia patients with inhibitors to FVIII (hemophilia A) or IX (hemophilia B), patients with congenital and acquired hemophilia and in patients with FVII deficiency or Glantzmann thrombasthenia (last indication is approved only in Europe). Off-labeled, the drug has been prescribed for prevention, or treatment of bleeding in severe hepatic disease, neonatal coagulopathies, high-risk surgical procedures, trauma, thrombocytopenia and platelet function disorders, as well as for urgent reversal of oral anticoagulation. Here we report a case of a 53-year-old female patient with delayed graft function after kidney transplantation, who had kidney biopsy complicated with prolonged bleeding. After unsuccessful treatment with desmopressin, the patient was treated with rFVIIa and the bleeding stopped immediately. Only few anecdotal reports of use of rFVIIa for treatment of bleeding in uremic patients have been published thus far. To our knowledge, this is the first case that describes use of rFVIIa for management of bleeding as a complication of renal biopsy in a uremic patient in the early kidney posttransplantation period.

A review of the clinical utility of INR to monitor and guide administration of prothrombin complex concentrate to orally anticoagulated patients

Background and objectivesThe number of patients treated with oral anticoagulation (OAC) is increasing and these patients are monitored by International Normalized Ratio (INR). Bleeding complications are common and we speculate if this is related to the limitation of INR only reflecting the initiation steps of the haemostatic process. The objective of the present review was to reassess the evidence for using INR as a tool to guide administration of prothrombin complex concentrates (PCC) to OAC patients. A Medline and Cochrane database search was conducted using the following keywords: prothrombin complex concentrate, reversal of oral anticoagulation and international normalized ratio (INR). Thirty-three articles were contracted and a total of ten studies were eligible after applying inclusion and exclusion criteria encompassing only 339 patients. No consensus regarding optimal target INR value to aim for when reversing OAC was found. In three of the studies it was reported that patients reaching their target INR continued to bleed, whereas three studies reviewed reported good haemostatic response also in patients that did not reach their target INR. The present review found limited evidence for the usefulness of INR as a tool to monitor and guide reversal of OAC induced coagulopathy in patients with PCC, which is expected given that it is a plasma-based assay only reflecting a limited part of the haemostatic process.

Practical management for urgent reversal of oral anticoagulation in patients with acute intracerebral haemorrhage

In case of intracerebral haemorrhage (ICH) during oral anticoagulant therapy (OAT) it is mandatory to obtain the fast and complete normalisation of haemostasis, in order to minimise the risk of haematoma enlargement. Furthermore, if neurosurgery is requested, the immediate correction of haemostatic balance allows the execution of emergency intervention, thus reducing the risk of intra- and post-surgical haemorrhagic complications. Currently prothrombin complex concentrate (PCC) in combination with vitamin K represents the gold standard treatment for patients with ICH during OAT. This treatment should be preferred to the administration of fresh frozen plasma (FFP) in order to guarantee a fast and almost immediate normalisation of blood coagulation.

Practical management for urgent reversal of oral anticoagulation in patients with acute intracerebral haemorrhage

In case of intracerebral haemorrhage (ICH) during oral anticoagulant therapy (OAT) it is mandatory to obtain the fast and complete normalisation of haemostasis, in order to minimise the risk of haematoma enlargement. Furthermore, if neurosurgery is requested, the immediate correction of haemostatic balance allows the execution of emergency intervention, thus reducing the risk of intra- and post-surgical haemorrhagic complications. Currently prothrombin complex concentrate (PCC) in combination with vitamin K represents the gold standard treatment for patients with ICH during OAT. This treatment should be preferred to the administration of fresh frozen plasma (FFP) in order to guarantee a fast and almost immediate normalisation of blood coagulation.

Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage.

Intracranial haemorrhage is a serious and potentially fatal complication of oral anticoagulant therapy. Prothrombin complex concentrates can substantially shorten the time needed to reverse the effects of oral anticoagulants. The aim of this study was to determine the efficacy and safety of a prothrombin complex concentrate for rapid reversal of oral anticoagulant therapy in patients with intracranial haemorrhage. Patients receiving oral anticoagulant therapy and suffering from acute intracranial haemorrhage were eligible for this prospective cohort study if their International Normalised Ratio (INR) was higher than or equal to 2.0. The prothrombin complex concentrate was infused at doses of 35-50 IU/kg, stratified according to the initial INR. Forty-six patients (25 males; mean age: 75 years; range 38-92 years) were enrolled. The median INR at presentation was 3.5 (range, 2-9). At 30 minutes after administration of the prothrombin complex concentrate, the median INR was 1.3 (range, 0.9-3), and the INR then declined to less than or equal to 1.5 in 75% of patients. The benefit of the prothrombin complex concentrate was maintained for a long time, since the median INR remained lower than or equal to 1.5 (median, 1.16; range, 0.9-2.2) at 96% of all post-infusion time-points up to 96 hours. No thrombotic complications or significant adverse events were observed during hospitalisation; six patients (13%) died, but none of these deaths was judged to be related to administration of the prothrombin complex concentrate. Prothrombin complex concentrates are an effective, rapid and safe treatment for the urgent reversal of oral anticoagulation in patients with intracranial haemorrhage. Broader use of prothrombin complex concentrates in this clinical setting appears to be appropriate.

Reversing coumadin: old and new choices

Oral anticoagulants, such as Coumadin, are among the most widely prescribed medications worldwide. With an aging population, the number of individuals taking oral anticoagulants continues to increase. Approximately 20% of patients on long-term oral anti-coagulation experience some form of unexpected bleeding and serious bleeding occurs in up to 2% of patients. Reversal of anticoagulation is considered for those patients with extreme elevation of the international normalised ratio (INR), those who are about to undergo a surgical procedure, or those who are bleeding. This presentation will review the options for reversing Coumadin anticoagulation with emphasis on the proper use of vitamin K and Fresh Frozen Plasma and also on the role of Prothrombin Complex Concentrates and recombinant factor 7a. Using a series of cases and specific treatment choices for the audience, the presentation is intended to highlight the balance of risks and benefits related to reversal of oral anticoagulants. Newer oral anticoagulants targeting inhibition of factor Xa or thrombin are on the near horizon and will bring with them new challenges for rapid reversal in the critically ill patient.

Fast Point-of-Care Coagulometer Guided Reversal of Oral Anticoagulation at the Bedside Hastens Management of Acute Subdural Hemorrhage

Emergency reversal of the international normalized ratio (INR) in patients who develop nontraumatic subdural hemorrhage (SDH) due to oral anticoagulants (OAC) represents a primary treatment strategy but it is difficult to predict the amount of prothrombin complex concentrate (PCC) needed for reversal treatment. Moreover, repeated INR testings in central laboratories (CL) are time consuming. The usefulness of point-of-care INR coagulometers (POC) to test the success of INR reversal in OAC-SDH has not yet been investigated. Prospectively, INR reversal was performed by administering PCC to patients suffering from acute SDH-OAC using a predefined dosing schedule. Accuracy and time gained by using POC were assessed and compared with CL measurements. A total of 10 patients were treated according to the protocol (male: 5). Bland-Altman analysis between POC and CL revealed a mean INR deviation of 0.013 for initial INR values and of 0.081 during reversal treatment. Using POC, the median initial net time gain (accounting for clinical examination and CT) for the start of PCC was 21 min. Median total time for POC-documented reversal was 27 min, as compared to 70 min for CL. The shortest interval between head CT and start of emergency SDH evacuation surgery was 37 min. By employing stepwise POC-guided reversal of the anticoagulatory effect of OAC, the calculated PCC dose could be reduced by 25% in the median. Using POC to measure INR values and patient-adapted PCC administration is a fast and economic method to reverse anticoagulation in patients with acute OAC-SDH.

Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study

Fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC) reverse oral anticoagulants. We compared PCC and FFP intraoperative administration in patients undergoing heart surgery with cardiopulmonary bypass (CPB). Forty patients [with international normalized ratio (INR)≥ 2·1] assigned semi-urgent cardiac surgery were randomized to receive either FFP (n = 20) or PCC (n = 20). Prior to CPB, they received either 2 units of FFP or half of the PCC dose calculated according to body weight, initial INR and target INR ( ≤ 1·5). After CPB and protamine administration, patients received either another 2 units of FFP or the other half PCC dose. Additional doses were administered if INR was still too high ( ≥ 1·5). Fifteen minutes after CPB, more patients reached INR target with PCC (P = 0·007): 7/16 patients vs. 0/15 patients with FFP; there was no difference 1 h after CPB (6/15 patients with PCC vs. 4/15 patients with FFP reached target). Fifteen minutes after CPB, median INR (range) decreased to 1·6 (1·2-2·2) with PCC vs. 2·3 (1·5-3·5) with FFP; 1 h after CPB both groups reached similar values [1·6 (1·3-2·2) with PCC and 1·7 (1·3-2·7) with FFP]. With PCC, less patients needed additional dose (6/20) than with FFP (20/20) (P < 0·001). Both groups differed significantly on the course of factor II (P = 0·0023) and factor X (P = 0·008) over time. Dilution of coagulation factors was maximal at CPB onset. Safety was good for both groups, with only two related oozing cases with FFP. PCC reverses anticoagulation safely, faster and with less bleeding than FFP.

Recommendations for the Use of Therapeutic Plasma

Four approved plasma preparations are available in most European countries: fresh frozen plasma, lyophilized plasma, solvent/detergent(SD)-treated plasma and methylene blue/light-treated plasma. Evidence of the clinical efficacy of plasma is mainly based on controlled or uncontrolled observational studies, case reports or expert opinion. As definitions of evidence grades used in previous guidelines and recommendations are sophisticated and difficult to apply to clinical routine, we established a simple system involving 2 recommendation strengths (1 and 2) and 3 evidence grades (A, B, C). Plasma is indicated for complex coagulopathy associated with manifest or imminent bleeding, particularly microvascular bleeding, in massive transfusion, disseminated intravascular coagulation and liver disease. With the exception of emergency situations when clotting assay results are not available on time, a clinically relevant coagulopathy must be verified before plasma is administered. The rapid infusion of at least 10 ml of plasma per kg of body weight is required to increase the respective clotting factor or inhibitor levels significantly. Therapeutic plasma exchange with 40 ml of plasma per kg of body weight is the treatment of first choice in acute thrombotic-thrombocytopenic purpura (TTP) or adult hemolytic uremic syndrome (HUS). Rare indications are congenital factor V or FXI deficiency, plasma exchange in neonates with severe hemolysis or hyperbilirubinemia, and filling of the oxygenator in extracorporeal membrane oxygenation in neonates. Prothrombin complex concentrates should be preferred to plasma for the rapid reversal of oral anticoagulation, since plasma is less efficient in this setting. Side effects resulting from the administration of plasma are rare but have to be considered.