Target For New Anticoagulants Research Articles

Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial

Individuals with kidney failure undergoing hemodialysis are at elevated risk for thromboembolic events. Factor (F) XI, which is in the intrinsic pathway of coagulation, is emerging as an attractive target for new anticoagulants that may be safer than existing agents. Osocimab—an inhibitory FXIa antibody—is a potential treatment option for such patients. We conducted a phase 2b, double-blind, placebo-controlled trial, in which 704 participants (448 male, 256 female) with kidney failure undergoing hemodialysis were randomized to receive lower- or higher-dose osocimab or placebo. In total, 686 participants (436 male, 250 female) received treatment for ≤18 months (planned minimal treatment period of 6 months). The co-primary outcomes were clinically relevant bleeding (a composite of major and clinically relevant nonmajor bleeding) and a composite of the incidence of moderate, severe or serious adverse events. Clinically relevant bleeding occurred in 16/232 (6.9%) and 11/224 (4.9%) participants who received lower- and higher-dose osocimab, respectively, and in 18/230 participants (7.8%) who received a placebo. For the composite adverse event endpoint, incidences were 51%, 47% and 43% in the lower-dose osocimab, higher-dose osocimab and placebo groups, respectively. These results suggest that osocimab is associated with a low risk of bleeding and is generally well tolerated in this population; findings that require confirmation in larger trials. ClinicalTrials.gov identifier, NCT04523220.

Selected highlights in angiology and haemostasis for the year 2021

Several topics among those that marked the year 2021 are discussed in this article. Factor XI represents an original target for new anticoagulants, and the first results of a phase 2 study of prophylaxis after knee replacement surgery are very promising. A real-life study confirms that the pulmonary embolism exclusion strategy using an age-adjusted D-dimer cut-off is safe and increases the diagnostic yield. Several studies of tranexamic acid provide further insight into the indications for its use and highlight some potential risks. Finally, the concerns regarding a potential risk of increased mortality related to paclitaxel-eluting technology used in lower limb revascularisation are questioned by the results of the latest trials.

Factor XI as a Target for New Anticoagulants.

Despite advances in anticoagulant therapy, thrombosis remains the leading cause of morbidity and mortality worldwide. Heparin and vitamin K antagonists (VKAs), the first anticoagulants to be used successfully for the prevention and treatment of thrombosis, are associated with a risk of bleeding. These agents target multiple coagulation factors. Thus, by activating antithrombin, heparin mainly inhibits factor Xa and thrombin, whereas VKAs lower the levels of the vitamin K-dependent clotting factors. Direct oral anticoagulants, which have replaced VKAs for many indications, inhibit only factor Xa or thrombin. Although the direct oral anticoagulants are associated with less bleeding than VKAs, bleeding remains their major side effect. Epidemiological and animal studies have identified factor XI as a target for potentially safer anticoagulant drugs because factor XI deficiency or inhibition protects against thrombosis and is associated with little or no bleeding. Several factor XI-directed strategies are currently under investigation. This article (1) reviews the rationale for the development of factor XI inhibitors, (2) identifies the agents in most advanced stages of development, (3) describes the results of completed clinical trials and provides a summary of those underway, and (4) highlights the opportunities and challenges for this next generation of anticoagulants.

Advances in Antithrombotic Therapy.

Thrombosis remains a major cause of morbidity and mortality. Consequently, advances in antithrombotic therapy are needed to reduce the disease burden. This article focuses on 2 such advances. First, the prevention of atherothrombosis in patients with coronary or peripheral artery disease, which has been enhanced by the finding that the combination of low-dose rivaroxaban plus aspirin is superior to aspirin alone for prevention of recurrent ischemic events. However, this benefit comes at the cost of increased bleeding albeit not fatal bleeding. To overcome this problem, the second advance is the identification of factor XI as a target for new anticoagulants that are potentially safer than those currently available.

Anticoagulants: current topics

Despite the introduction of direct oral anticoagulants (DOAC), the need for more effective and safer antithrombotic strategies exists. Recently, the findings stating that the contact system is important for thrombus formation has identified factor XI as a potential target for new anticoagulants. Approximately 20-30% of patients who develop venous thromboembolism (VTE) also have cancer. To date, the drugs primarily used in the treatment of VTE are heparin in the acute phase and warfarin in the chronic phase. Recently, a large-scale international clinical trial, which examined the composite outcomes of VTE recurrence and major bleeding in cancer patients, found that edoxaban, a direct factor Xa inhibitor, is not inferior to low-molecular-weight heparin. The study also showed that DOACs have a promising potential to prove therapeutically effective in future studies. Anticoagulants are associated with a severe side effect, bleeding, which makes emergency neutralization an important concern. Four-factor prothrombin complex concentrate can be used to reverse the effect of warfarin and could also be effective as a neutralizing agent in patients having received DOACs. Moreover, more specific reversing agents include the approved human monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran.

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis: Factor XI as a Target for New Anticoagulants.

The goal of anticoagulant therapy is to attenuate thrombosis without compromising hemostasis. Although the direct oral anticoagulants are associated with less intracranial hemorrhage than vitamin K antagonists, bleeding remains their major side effect. Factor XI has emerged as a promising target for anticoagulants that may be safer than those currently available. The focus on factor XI stems from epidemiological evidence of its role in thrombosis, the observation of attenuated thrombosis in factor XI-deficient mice, identification of novel activators, and the fact that factor XI deficiency is associated with only a mild bleeding diathesis. Proof-of-concept comes from the demonstration that compared with enoxaparin, factor XI knockdown reduces venous thromboembolism without increasing bleeding after elective knee arthroplasty. This article rationalizes the selection of factor XI as a target for new anticoagulants, reviews the agents under development, and outlines a potential path forward for their development.

Factors XI and XII as Targets for New Anticoagulants.

Compared with vitamin K antagonists, the direct oral anticoagulants (DOACs) are simpler to administer and are associated with less intracranial bleeding. Nonetheless, even with the DOACs, bleeding still occurs and many patients with atrial fibrillation fail to receive anticoagulant thromboprophylaxis because of the fear of bleeding. Therefore, there is an urgent need for safer anticoagulants. Recent investigations into the biochemistry of hemostasis and thrombosis have identified new targets for development of novel anticoagulants. Using data from complementary sources, including epidemiological studies and investigations in various animal models, the contact pathway has emerged as a potential mediator of thrombosis that plays a minor part in hemostasis. Consequently, factor (F) XII of the contact system and FXI in the intrinsic pathway have been identified as potentially safer targets of anticoagulation than thrombin or FXa. However, further studies are needed to identify which is the better target for the appropriate indication. This review highlights the evidence for focusing on FXI and FXII and examines the novel approaches directed at these new targets. These emerging strategies should address current unmet medical needs and provide new avenues by which to improve anticoagulant therapy by reducing the risk of bleeding.

Emerging anticoagulant strategies

AbstractDespite the introduction of direct oral anticoagulants (DOACs), the search for more effective and safer antithrombotic strategies continues. Better understanding of the pathogenesis of thrombosis has fostered 2 new approaches to achieving this goal. First, evidence that thrombin may be as important as platelets to thrombosis at sites of arterial injury and that platelets contribute to venous thrombosis has prompted trials comparing anticoagulants with aspirin for secondary prevention in arterial thrombosis and aspirin with anticoagulants for primary and secondary prevention of venous thrombosis. These studies will help identify novel treatment strategies. Second, emerging data that naturally occurring polyphosphates activate the contact system and that this system is critical for thrombus stabilization and growth have identified factor XII (FXII) and FXI as targets for new anticoagulants that may be even safer than the DOACs. Studies are needed to determine whether FXI or FXII is the better target and to compare the efficacy and safety of these new strategies with current standards of care for the prevention or treatment of thrombosis. Focusing on these advances, this article outlines how treatment strategies for thrombosis are evolving and describes the rationale and approaches to targeting FXII and FXI. These emerging anticoagulant strategies should address unmet needs and reduce the systemic underuse of anticoagulation because of the fear of bleeding.

Factor XI and factor XII as targets for new anticoagulants

Although the non-vitamin antagonist oral anticoagulants produce less intracranial bleeding than warfarin, serious bleeding still occurs. Therefore, the search for safer anticoagulants continues. Factor XII and factor XI have emerged as promising targets whose inhibition has the potential to prevent thrombosis with little or no disruption of hemostasis. Thus, thrombosis is attenuated in mice deficient in factor XII or factor XI and patients with congenital factor XII deficiency do not bleed and those with factor XI deficiency rarely have spontaneous bleeding. Strategies targeting factor XII and XI include antisense oligonucleotides to decrease their synthesis, inhibitory antibodies or aptamers, and small molecule inhibitors. These strategies attenuate thrombosis in various animal models and factor XI knockdown with an antisense oligonucleotide in patients undergoing knee replacement surgery reduced postoperative venous thromboembolism to a greater extent than enoxaparin without increasing bleeding. Therefore, current efforts are focused on evaluating the efficacy and safety of factor XII and factor XI directed anticoagulant strategies.

The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor

The activated serine protease factor Xa is a promising target for new anticoagulants. After studies on naturally occurring factor Xa inhibitors indicated that such agents could be effective and safe, research focused on small-molecule direct inhibitors of factor Xa that might address the major clinical need for improved oral anticoagulants. In 2008, rivaroxaban (Xarelto; Bayer HealthCare) became the first such compound to be approved for clinical use. This article presents the history of rivaroxaban's development, from the structure-activity relationship studies that led to its discovery to the preclinical and clinical studies, and also provides a brief overview of other oral anticoagulants in advanced clinical development.

HD1, a thrombin- and prothrombin-binding DNA aptamer, inhibits thrombin generation by attenuating prothrombin activation and thrombin feedback reactions

HD1, a DNA aptamer, binds exosite 1 on thrombin and blocks its clotting activity. Because HD1 also binds prothrombin and inhibits its activation by prothrombinase, we hypothesised that HD1 would be a more potent inhibitor of coagulation than other exosite 1-directed ligands, such as Hir(54-65)(SO(3)(-)). Supporting this concept, the effect of HD1 on the prothrombin time and activated partial thromboplastin time was two-fold greater than that of Hir(54-65)(SO(3)(-)) even though both agents inhibited thrombin-mediated factor (F) V and FVIII activation to a similar extent. In thrombin generation assays, HD1 (a) delayed the lag time, (b) reduced peak thrombin concentration, and (c) decreased endogenous thrombin potential to a greater extent than Hir54-65(SO(3)(-)). To eliminate thrombin feedback, studies were repeated in FV- and/or FVIII-deficient plasma supplemented with FVa and/or FVIIIa. Only HD1 prolonged the lag time in FV- and FVIII-deficient plasma supplemented with FVa and FVIIIa. In contrast, HD1 and Hir54-65(SO(3)(-)) inhibited the lag time in FVIII-deficient plasma supplemented with FVIIIa and in normal plasma. The more potent anticoagulant properties of HD1, therefore, reflect its capacity to attenuate FV activation by thrombin and inhibit prothrombinase assembly. These findings identify prothrombin as a potential target for new anticoagulants.

Another oral thrombin inhibitor for stroke prevention in atrial fibrillation?

Atrial fibrillation (AF), the most common arrhythmia, is associated with a five-fold increase in the risk of stroke (1). Furthermore, cardio-embolic strokes in AF patients tend to be severe, and are often fatal or associated with serious morbidity. Vitamin K antagonists, such as warfarin, produce about a 64% reduction in the risk of stroke in AF patients (2), but have numerous limitations that curtail their uptake and diminish their effectiveness. These limitations include a slow onset of action, a variable dose requirement, reflecting common genetic polymorphisms that influence their metabolism, and an unpredictable anticoagulant response because of differences in dietary vitamin K intake and numerous drug-drug interactions, which increase or decrease the anticoagulant effect (3). With the anticoagulant response so variable, routine monitoring is necessary to ensure that the international normalised ratio (INR) is therapeutic because overanticoagulation is associated with an increased risk of haemorrhage, whereas under-anticoagulation increases the risk of thrombosis. Such monitoring is inconvenient for patients and physicians and costly for the healthcare system. Because of the complexity of management, only about one-half of eligible patients with AF receive warfarin, and among those who receive such treatment, the INR is frequently outside of the therapeutic range (4). The large unmet need caused by the limitations of warfarin has prompted the development of new oral anticoagulants with potential advantages over existing agents. Ximelagatran, the first oral thrombin inhibitor, was effective for stroke prevention in patients with AF, but was withdrawn in 2006 because of potential hepatic toxicity (5). The effectiveness of ximelagatran prompted development of a second generation of oral thrombin inhibitors. The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial demonstrated the effectiveness of dabigatran etexilate, the first of this new generation, for stroke prevention in AF, endorsing thrombin as an appropriate target for new anticoagulants. Two doses of dabigatran etexilate were compared with warfarin in this trial; the higher dose regimen (150 mg twice-daily) was associated with significantly fewer intracranial bleeds and strokes compared with warfarin, whereas the lower dose (110 mg twice-daily) was associated with significantly less major bleeding than warfarin and similar efficacy (6). AZD0837 is the second of the new generation of oral thrombin inhibitors. A follow-up of ximelagatran, AZD0837 is a prodrug of AR-H067637, a selective and reversible inhibitor of free and fibrin-bound thrombin (7). Cytochrome P450 isoenzymes in the liver convert AZD0837 to AR-H069927, an intermediate that undergoes further metabolism to AR-H067637, the active form. In healthy individuals, AR-H067637 has a plasma half-life of 9–14 hours and the drug is cleared in the urine and faeces. An immediate-release preparation was the first formulation of AZD0837 evaluated in clinical trials; a more recent extended-release formulation enables once-daily dosing. In this issue of Thrombosis and Haemostasis, Olsson et al. (8) report the results of a phase II, randomised, controlled, dosefinding study evaluating the safety and tolCorrespondence to: Dr. Jeffrey Weitz Henderson Research Centre 711 Concession Street Hamilton, Ontario L8V 1C3, Canada Tel.: +1 905 574 8550, Fax: +1 905 575 2646 E-mail: jweitz@thrombosis.hhscr.org

What can ongoing clinical trials of anticoagulants demonstrate?

As the population ages, the burden of thromboembolic disease increases. The development of new anticoagulants that overcome the shortcomings of the vitamin K antagonists represents an important advance.Clinical evaluation of new anticoagulants typically begins in short-term indications, such as prophylaxis against venous thromboembolism in patients undergoing orthopaedic surgery, followed by investigation in chronic conditions, such as stroke prevention in patients with atrial fibrillation. Factors for consideration in clinical trials include methodological issues (blinded versus open-label; active-control statistical designs; patient selection, etc.). Despite its subsequent withdrawal, clinical trials of ximelagatran demonstrated the efficacy of fixed doses of an oral, direct thrombin inhibitor for prevention of thromboembolism. Direct and indirect inhibition of activated Factor X is another target for new anticoagulants. Evidence-based data from trials such as these will pave the way for new anticoagulants, with the goal of bringing optimum prophylactic therapy to those requiring anticoagulation.

Warfarin replacements: Mechanisms underlying emerging agents

Warfarin is effective for the prevention and treatment of thromboembolic disorders. However, warfarin has a narrow therapeutic window, unpredictable pharmacology, and food and drug interactions that require regular monitoring and dose adjustment. Therefore, there is a clear need for new anticoagulants that can overcome these limitations. There are a number of potential targets for new anticoagulants within the coagulation cascade; factor Xa and thrombin are particularly attractive options. There are numerous drugs in development that directly target either factor Xa or thrombin, and have predictable pharmacology, meaning monitoring is unlikely to be required. Dabigatran, apixaban and rivaroxaban are in advanced development for a number of indications including prevention and treatment of venous thromboembolism and prevention of stroke in patients with atrial fibrillation. In the near future, these drugs may be able to offer an alternative to warfarin, providing patients with convenient and effective anticoagulation.

Pharmacology and Clinical Potential of Direct Thrombin Inhibitors

Direct thrombin inhibitors represent a new class of anticoagulants that bind directly to thrombin and block the enzyme's interactions with its substrates. These agents have been developed, at least in part, to overcome the limitations of heparin and vitamin K antagonists. This paper (a) reviews why thrombin is an ideal target for new anticoagulants, (b) describes the pharmacological profiles of the various direct thrombin inhibitors, (c) outlines the potential mechanistic advantages of parenteral direct thrombin inhibitors over heparin, (d) defines the potential benefits of ximelagatran, the first orally active direct thrombin inhibitor, over vitamin K antagonists, and (e) provides clinical perspective on the strengths and weaknesses of the various parenteral and oral direct thrombin inhibitors.

Ximelagatran: the first oral direct thrombin inhibitor

Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.

Ximelagatran: the first oral direct thrombin inhibitor

Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.

An Update on New Anticoagulants

A variety of new anticoagulants for the prevention and treatment of venous and arterial thromboembolism are under development. Designed to overcome the limitations of heparin and vitamin K antagonists, these new agents are at various stages of clinical testing. This paper reviews venous and arterial thrombogenesis, discusses the regulation of coagulation, identifies the molecular targets for new anticoagulants, describes new anticoagulants in more advanced stages of clinical testing, and provides perspective on how these agents will impact on practice.

New anticoagulants.

The limitations of heparin and warfarin have prompted the search for new anticoagulants for the prevention and treatment of venous and arterial thromboembolism. Although many such agents are in development, only a few have reached phase II or higher levels of clinical testing. This article reviews venous and arterial thrombogenesis, discusses the regulation of coagulation, identifies the molecular targets for new anticoagulants currently under development, describes the agents in more advanced stages of clinical testing, and provides clinical perspective on the opportunities for new anticoagulant drugs.

Orally active direct thrombin inhibitors.

Anticoagulants are widely used for the prevention and treatment of venous and arterial thrombosis. Current treatment strategies often employ a combination of parenteral and oral agents because the only available orally active anticoagulants, vitamin K antagonists, have a delayed onset of action. Furthermore, vitamin K antagonists have a narrow therapeutic window that necessitates careful anticoagulation monitoring, and dosing is problematic because of multiple food and drug interactions. These limitations highlight the need for oral anticoagulants that produce a more predictable anticoagulant response than vitamin K antagonists, thereby obviating the need for laboratory monitoring. Ximelagatran has the potential to meet this need. A prodrug of melagatran, an agent that targets thrombin, ximelagatran exhibits many of the characteristics of an ideal anticoagulant. This article (1). reviews the limitations of vitamin K antagonists, (2). lists the characteristics of an ideal anticoagulant, (3). rationalizes thrombin as a target for new anticoagulants, (4). reviews the preclinical and clinical data with ximelagatran, and (5). provides clinical perspective as to the future of ximelagatran and other orally active anticoagulants currently under development.