Universal,class-specific and drug-specific reversal agents for the new oral anticoagulants

Although there is controversy about the absolute need for a reversal agent for the new direct oral anticoagulants (DOACs), the absence of such an agent is a barrier to more widespread use of these agents. For the management of major life-threatening bleeding with the DOACs, most authorities recommend the use of four factor prothrombin complex concentrates, although the evidence to support their use in terms of improving outcomes is meager. At the present time, there are three antidotes in development and poised to enter the market. Idarucizumab is a drug-specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran. Andexanet alfa is a class-specific antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor, enoxaparin. Ciraparantag is a universal antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor, enoxaparin.     

Managing acute bleeds in the patient with haemophilia and inhibitors: options, efficacy and safety

Summary.  The options available for treating the patient with haemophilia and inhibitors undergoing surgery or with other acute bleeds include high-dose factor VIII (FVIII) (human or porcine), prothrombin complex concentrates (PCCs), activated PCCs (aPCCs), recombinant activated factor VII (rFVIIa), and factor replacement combined with immunoadsorption or immunosuppression. Human FVIII is effective in patients with low-titre inhibitors. Porcine FVIII is currently not available, and PCCs and aPCCs, although effective, have been associated with a high incidence of adverse events. Immunoadsorption and immunosuppression offer excellent long-term solutions, but the duration of these techniques makes them less attractive for use in acute settings. Recombinant FVIIa has demonstrated excellent efficacy and safety, even in patients refractory to other therapies.     

Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography.

Bleeding is the major adverse reaction to anticoagulants, leading to significant morbidity and even mortality. Protamine is a specific antidote for heparin yet is only partially effective for enoxaparin, and the activated factor X inhibitor fondaparinux and the direct thrombin inhibitors argatroban and bivalirudin lack specific antidotes. We evaluated the ability of recombinant activated factor VII (rFVIIa), a general hemostatic agent, to reverse the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, as measured by thromboelastography. Whole-blood samples containing each test anticoagulant, with or without rFVIIa 1.5-4.5 microg/ml, were prepared ex vivo (n >or= 48, each anticoagulant) and analyzed by thromboelastography. The thromboelastography parameters of clot initiation, propagation, rigidity and elasticity were compared for the ex-vivo samples for each anticoagulant. The reversal ability of rFVIIa was also assessed using the standard clinical assay used to monitor each anticoagulant. Thromboelastography was performed on blood from eight stably anticoagulated patients, with and without exogenous rFVIIa. For each anticoagulant, rFVIIa significantly improved and, in some cases, completely normalized all thromboelastography parameters (P < 0.001). rFVIIa significantly (P < 0.01) decreased the activated partial thromboplastin time for argatroban-containing, bivalirudin-containing, or heparin-containing blood yet did not affect the anti-activated factor X levels for enoxaparin-containing or fondaparinux-containing blood. By thromboelastography, rFVIIa exerted generally similar reversal effects on the anticoagulated patient samples as on the ex-vivo samples. In conclusion, rFVIIa effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, and should be considered for patients with excessive bleeding associated with these anticoagulants.     

Emergency reversal of antithrombotic treatment

The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In case of serious or even life-threatening bleeding in a patient who uses anticoagulant agents or when a patient on anticoagulants needs to undergo an urgent invasive procedure, anticoagulant treatment can be reversed by various specific strategies. Heparin and heparin derivatives can be counteracted by protamine sulphate, whereas the anticoagulant effect of vitamin K antagonists may be neutralized by administration of vitamin K or prothrombin complex concentrates. The anti-hemostatic effect of aspirin and other anti-platelet strategies can be corrected by the administration of platelet concentrate or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors has been introduced and most of these agents are presently being evaluated in clinical studies. The new generation anticoagulants include specific inhibitors of factor IIa, factor Xa (including pentasaccharides) and agents that interfere with tissue factor activity. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although in some cases the administration of recombinant factor VIIa may be an option.     

Newer clinically available antithrombotics and their antidotes

New oral anticoagulants (NOACs) have emerged as an alternative therapy to warfarin in the treatment of arterial and venous thromboembolism and in stroke prevention in patients with non-valvular atrial fibrillation (AF). Three of them, i.e., dabigatran, rivaroxaban, and apixaban, have been approved for clinical use in North America and in a number of European countries. In non-valvular AF, their approval was based on large randomized trials showing that they are non-inferior or even, in some instances, superior to warfarin. Dabigatran is a direct thrombin (factor IIa) inhibitor; rivaroxaban and apixaban are direct factor Xa inhibitors. Before using NOACs, it is recommended to become familiar with their pharmacological characteristics and their metabolism. The absence of specific antidotes is often cited as part of the possible weaknesses of NOACs. Antidotes are perceived to be useful in emergency situations such as life-threatening bleeding or non-elective major surgery. NOACs do not require blood monitoring, and therefore, patient compliance to the treatment is essential. For the present time, there are no specific antidotes available for the three NOACs approved for clinical use. However, phase I or phase II research studies in this area are ongoing. For dabigatran, a specific antidote has been tested in a rat model of anticoagulation, and a study in healthy male volunteers has been recently reported. For rivaroxaban, prothrombin complex concentrates (PCCs) have been found to completely reverse the prolongation of the prothrombin time induced by this NOAC. For apixaban, recombinant factor VII was found in an experimental study using human blood to be superior to activated PCC (aPCC) and PCC. More specific antidotes for rivaroxaban and apixaban are in phases I and II evaluation. The management of patients suffering from a major bleeding or requiring a non-elective major surgery includes non-specific reversal agents and is discussed in the light of a recent position paper and of current literature. Most recommendations are based on expert opinions only as randomized trials using agents for reversal of anticoagulation in case of life-threatening bleeding or of major urgent surgery are not available.     

Control of bleeding in patients with haemophilia A with inhibitors: a systematic review

This paper reports a systematic review of the best available evidence of clinical effectiveness in the treatment of acute bleeding in haemophilia A patients with inhibitors. Because of the lack of randomized controlled trials (RCTs) on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. Because of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. No evidence was found to support the use of high-dose factor VIII (FVIII) in bleeding episodes. However in surgery it was found to be highly successful (100%) for low-titre, low-responding inhibitors although not reliable for high-responding inhibitors. Porcine FVIII (pFVIII) was effective in the control of severe bleeding episodes with high-titre or high-responding inhibitors (100%) and in 60-90% of surgical procedures. Activated prothrombin complex concentrates (APCCs) appear to be more effective than prothrombin complex concentrates (PCCs) in the control of mild to severe bleeding episodes. There was no good evidence for the use of PCCs in surgery. APCCs controlled bleeding in approximately 90% of surgical episodes. Recombinant factor VIIa (rFVIIa) controlled 70-100% of mild to severe bleeding episodes with high-responding inhibitors, and achieved better results when used early. It was effective in 60-100% of surgical episodes. Doses varied from study to study, and side-effects from mild to infrequent but serious adverse events were reported. The quality of the evidence is variable. Limited evidence relating to other treatment options is also included in the review.     

Laboratory measurement of the direct oral anticoagulants

Direct oral anticoagulants (DOACs), including the direct thrombin inhibitor, dabigatran, and the direct factor Xa (FXa) inhibitors, rivaroxaban, apixaban and edoxaban, are approved for thromboembolism prevention and treatment. These drugs do not require routine coagulation monitoring but, in some circumstances, measurement of drug level or anticoagulant effect may be necessary. Although traditional coagulation tests lack analytical sensitivity and specificity, they are widely available and inexpensive, and can provide useful information regarding the residual anticoagulant effect of DOACs. Hemoclot^® and ecarin‐based assays can be used to quantify dabigatran level and calibrated chromogenic anti‐FXa assays are suitable for measuring rivaroxaban, apixaban and edoxaban levels, but these tests are not yet widely available.     

Who,when, and how to reverse non-vitamin K oral anticoagulants

Non-vitamin K oral anticoagulants (NOACs) have been a major addition to our therapeutic armamentarium. They are at least as effective as warfarin in the thromboprophylaxis of non-valvular atrial fibrillation and management of thromboembolic disease, with a more favorable safety profile. Their predictable pharmacokinetics and pharmacodynamics allow for a fixed oral dosing without the need for anticoagulation monitoring. A major concern regarding NOACs is the lack of a readily available antidote to reverse their anticoagulation effect in case of life-threatening bleeding or need for emergent surgery. In this review, we summarize preclinical and clinical data on (a) hemostatic agents used to reverse NOACs, and (b) novel, target-specific NOACs reversal agents under development. The prothrombin complex concentrates, activated prothrombin complex concentrates and recombinant activated factor VII are hemostatic agents that have been assessed in reversing NOACs. Preclinical studies with hemostatic agents report variable results and there is only limited clinical data available to date. Idarucizumab and andexanet alfa are NOAC-specific reversal agents designed to reverse dabigatran and factor Xa inhibitors accordingly. Aripazine is a universal anticoagulation reversal agent. Preclinical studies show promising results and these agents are already in different stages of clinical development. Phase I and II clinical trials demonstrate efficacy in reversing NOACs without major side effects. Until these agents become commercially available, management of patients receiving NOACs who present with major bleeding or require emergent surgery should focus on (a) immediate discontinuation of NOACs, (b) supportive measures or postponing surgery for 12–24 h after the last NOAC dose, and/or (c) consideration of hemostatic agents.     

Stroke prevention in patients with atrial fibrillation—anticoagulation strategy 2012

Vitamin K antagonists have been recommended as the only available oral anticoagulants for stroke prevention in patients with atrial fibrillation for many years. Despite their proved effectiveness, there are several limitations and drawbacks of this therapy. Recently three major clinical trials of novel oral anticoagulants clinical trials have been published. Dabigatran, a direct thrombin inhibitor, as well as rivaroxaban and apixaban, direct Xa factor inhibitors, were found to have at least noninferior efficacy and safety in comparison to vitamin K antagonists for stroke prevention in patients with non-valvular fibrillation. These novel oral anticoagulants may constitute a valuable alternative to vitamin K antagonists.     

New anticoagulants and their potential impact on the treatment of thromboembolic disease

Traditional anticoagulants have drawbacks that make them complex to manage, limit their usefulness, and increase the possibility of adverse events. New anticoagulants are being developed that directly target a single coagulation factor. The agents have improved pharmacokinetics and pharmacodynamics and may not need coagulation monitoring. In addition, many are available orally. Agents that target factor Xa or factor IIa are the most advanced in development and of greatest interest. Fondaparinux and idraparinux are parenteral, specific, indirect, factor Xa inhibitors that have a mechanism of action similar to that of heparin. Idraparinux has a prolonged half-life and is dosed once weekly. Razaxaban is a small-molecule, oral, direct FXa inhibitor with demonstrated efficacy in orthopedic surgery for primary prevention of venous thromboembolism. Other oral Xa inhibitors are entering clinical trials. Ximelagatran is an oral factor IIa or thrombin inhibitor with documented efficacy for primary prevention of venous thromboembolism in orthopedic surgery, for the acute and chronic treatment of deep venous thrombosis and stroke prevention in atrial fibrillation. Other oral IIa inhibitors are entering clinical trials. Many of these agents will have a profound effect on the treatment of venous thromboembolism potentially resulting in reduced costs, improved patient satisfaction with treatment, and greater use of selected indications.     

Orthopaedic surgery in haemophilic patients with inhibitors: an overview

Our experience and a review of the literature on inhibitors have shown that, with the availability of recombinant factor VIIa (rFVIIa), haemophilic patients with high inhibitor titres requiring elective orthopaedic surgery can undergo such surgery with a high expectation of success. The advent of rFVIIa has made major elective orthopaedic surgery possible in haemophilic patients with high-titre inhibitors, resulting in an improved quality of life. Recombinant FVIIa appears to be an efficient haemostatic product for surgery in patients suffering from haemophilia A and B with inhibitors. The series of major elective orthopaedic surgical procedures using rFVIIa (n=53) is the largest ever reported in haemophilic patients with inhibitors, despite the long-standing presence of other treatment modalities, such as high-dose human factor VIII (FVIII), porcine FVIII (n=8), and prothrombin complex concentrates/activated prothrombin complex concentrates (n=9). Thorough analysis of each case as part of a multidisciplinary team will allow us to perform elective orthopaedic procedures in patients with inhibitors.     

New anticoagulants

Anticoagulants are pivotal agents for prevention and treatment of thromboembolic disorders. Limitations of existing anticoagulants, vitamin K antagonist and heparins, have led to the development of newer anticoagulant therapies. These anticoagulants have been designed to target specific coagulation enzymes or steps in the coagulation pathway. New anticoagulants that are under evaluation in clinical trials include: (1) inhibitors of the factor VIIa/tissue factor pathway; (2) factor Xa inhibitors, both indirect and direct; (3) activated protein C and soluble thrombomodulin; and (4) direct thrombin inhibitors. Although most of these are parenteral agents, several of the direct inhibitors of factor Xa and thrombin are orally active. Clinical development of these therapies often starts with studies in the prevention of venous thrombosis before evaluation for other indications, such as prevention of cardioembolism in patients with atrial fibrillation or prosthetic heart valves. At present, the greatest clinical need is for an oral anticoagulant to replace warfarin for long-term prevention and treatment of patients with venous and arterial thrombosis. Ximelagatran, an oral direct thrombin inhibitor, is the first of a series of promising new agents that might fulfill this need. Large phase 3 trials evaluating ximelagatran for the secondary prevention of venous thromboembolism and prevention of cardioembolic events in patients with atrial fibrillation have been completed.     

Adjunctive pharmacologic therapy in percutaneous coronary intervention: part II anticoagulant therapy

Pharmacological adjuvant therapies to protect against procedure-related thrombotic complication are indispensable during percutaneous coronary intervention. In addition to antiplatelet therapy, use of anticoagulants to prevent acute thrombotic complication during percutaneous coronary intervention is essential. Besides unfractionated heparin (UFH), new anticoagulants have been developed and compared with UFH. Low-molecular weight heparins, direct thrombin inhibitors (e.g. bivalirudin), and recently developed agents such as fondaparinux (a factor Xa inhibitor) provide new alternatives to conventional UFH.     

Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors: a review of design,development and potential place in therapy

Direct oral anticoagulants are associated with rates of major bleeding which are not negligible, albeit lower than those associated with vitamin K antagonists. No specific reversal agent for factor Xa (FXa) direct inhibitors is currently available for clinical use. A modified activated human FXa decoy protein, andexanet alfa, is being developed that binds FXa direct inhibitors in their active site, thus reversing their anticoagulant effect. The purpose of this article is to review the design, development and clinical trials of andexanet alfa. Andexanet alfa was shown to reverse FXa inhibitors anticoagulant activity both in thrombosis animal models, healthy volunteers and patients with acute major bleeding. Andexanet alfa has been studied in double-blind, placebo-controlled phase II and III studies. A preliminary report of the phase III study showed that an effective hemostasis was obtained after andexanet alfa infusion in the majority of the patients with acute major bleeding associated with FXa inhibitors. Additional studies are ongoing and andexanet alfa is expected to be launched in the market in the near future.     

Newer anticoagulants in cardiovascular disease: a systematic review of the literature

Vitamin K antagonists (VKAs) such as warfarin have traditionally been the major therapeutic option for anticoagulation in clinical practice. VKAs are effective and extensively recommended for the prevention of venous and arterial thromboembolism in cardiovascular disease. Despite its effectiveness, warfarin is limited by factors such as a narrow therapeutic index, drug-drug interactions, food interactions, slow onset and offset of action, hemorrhage, and routine anticoagulation monitoring to maintain therapeutic international normalized ratio. During the last 2 decades, the approval of anticoagulants, such as low-molecular-weight heparins, indirect factor Xa inhibitors (eg, fondaparinux), and direct thrombin inhibitors (eg, argatroban, lepirudin, and desirudin), have expanded the number of available antithrombotic compounds with additional targets within the anticoagulation pathway. Although these medications offer several potential therapeutic advantages, they all require parenteral or subcutaneous administration and are substantially more expensive than VKAs. Thus, VKAs, despite several limitations, have remained the major option for most patients requiring chronic anticoagulation. These limitations have prompted interest in the development of newer oral anticoagulants. Novel anticoagulants targeting inhibition of factor Xa and thrombin (factor IIa) have now been incorporated into clinical practice based on the results of large randomized clinical trials, with the recent U.S. Food and Drug Administration approval of dabigatran for stroke prevention in atrial fibrillation and rivaroxaban for deep vein thrombosis and stroke prevention in atrial fibrillation, with multiple other agents in various stages of development for these and other indications. This review discusses the pharmacological properties, clinical results, and therapeutic applications of novel and new anticoagulants, thereby providing an outline for the future of anticoagulation in cardiovascular disease.     

Management of haemophilia in patients with high-titre inhibitors: focus on the evolution of activated prothrombin complex concentrate AUTOPLEX® T

Numerous therapeutic strategies have been applied to the management of patients with inhibitors to factors VIII or IX. Different treatment approaches are analysed including prothrombin complex concentrates (PCCs), activated prothrombin complex concentrates (aPCCs), porcine factor VIII concentrate, inhibitor neutralization, immune tolerance therapy, immunosuppressive regimens and recombinant factor VIIa. Clinical data are reported in the analysis of several treatments. PCCs and aPCCs have gained widespread acceptance as the standard first-line approach for patients with inhibitors. The aPCC AUTOPLEX® T has achieved a high response rate with a low level of thrombotic events. Four case studies are presented in which AUTOPLEX® T has been used successfully. Administration of platelet concentrate or, in elective surgery, waiting for inhibitor levels to decline are useful adjuncts to some treatments. The optimal treatment depends on the patient's inhibitor status – low responder (minimal or no increase in inhibitor levels upon administration of replacement clotting factor) or high responder (replacement clotting factor generates inhibitor production). A suggested algorithm for treating high-responder inhibitor patients is presented.     

Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors

Prothrombin complex concentrates (PCCs) and, more recently, activated prothrombin complex concentrates (APCCs), are widely used for the treatment of active bleeding in haemophiliacs with inhibitors. Myocardial infarction (MI), associated with the use of these concentrates, is a well-recognized, but uncommon, complication. We review the 14 previous cases published in the literature and describe two additional patients. MI related to the use of activated and non-activated PCCs predominantly affects young patients who often have no preceding history of, or risk factors for, MI and tends to be associated with large cumulative doses of concentrate. The most frequent pathological finding is myocardial haemorrhage, with no evidence of coronary artery atheroma or thrombosis. The management of further bleeding in these patients is difficult. We have safely used recombinant factor VIIa to treat bleeding in the immediate and long-term period following PCC-related MI.     

Determination of the anticoagulant effects of new oral anticoagulants: an unmet need

Thromboembolic diseases require anticoagulation for their prevention and treatment. New oral anticoagulants, specifically direct factor Xa and thrombin inhibitors, were developed to overcome the limitations of conventional anticoagulants. Their benefit has been demonstrated using fixed doses without laboratory-guided dose adjustment for patients following elective knee and hip replacement, treatment of venous thromboembolism and prevention of embolic events in atrial fibrillation. These anticoagulants are excreted by glomerular filtration at a rate of between 25 and 80%. Thus, lower doses are required for patients with impaired renal function. Therefore, determination of the anticoagulant effects may be needed in other specific patient populations. Prothrombin time, activated partial thromboplastin time, prothrombin-induced clotting time, ecarin clotting time, hemoclot assay, other specific coagulation assays and chromogenic substrate are available to determine the effect of the anticoagulants. Standardization of methods, development of point-of-care tests and identification of patient groups is ongoing.     

Activated protein C resistance testing for factor V Leiden

Activated protein C resistance assays can detect factor V Leiden with high accuracy, depending on the method used. Factor Xa inhibitors such as rivaroxaban and direct thrombin inhibitors including dabigatran, argatroban, and bivalirudin can cause falsely normal results. Lupus anticoagulants can cause incorrect results in most current assays. Assays that include dilution into factor V‐deficient plasma are needed to avoid interference from factor deficiencies or elevations, which can arise from a wide variety of conditions such as warfarin, liver dysfunction, or pregnancy. The pros and cons of the currently available assays are discussed. Am. J. Hematol. 89:1147–1150, 2014. © 2014 Wiley Periodicals, Inc.