key: cord-0815906-eijotv7k
authors: Mavromanoli, Anna C.; Barco, Stefano; Konstantinides, Stavros V.
title: Antithrombotics and new interventions for venous thromboembolism: Exploring possibilities beyond factor IIa and factor Xa inhibition
date: 2021-05-18
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12509
sha: 0ee2ab004b11934b330ed082c8b8d639240e59a9
doc_id: 815906
cord_uid: eijotv7k

Direct oral anti–activated factor X and antithrombin agents have largely replaced vitamin K antagonists as the standard of care in treatment of venous thromboembolism. However, gaps in efficacy and safety persist, notably in end‐stage renal disease, implantable heart valves or assist devices, extracorporeal support of the circulation, and antiphospholipid syndrome. Inhibition of coagulation factor XI (FXI) emerges as a promising new therapeutic target. Antisense oligonucleotides offer potential advantages as a prophylactic or therapeutic modality, with one dose‐finding trial in orthopedic surgery already published. In addition, monoclonal antibodies blocking activation and/or activity of activated factor XI are investigated, as are small‐molecule inhibitors with rapid offset of action. Further potential targets include upstream components of the contact pathway such as factor XII, polyphosphates, or kallikrein. Finally, catheter‐directed, pharmacomechanical antithrombotic strategies have been developed for high‐ and intermediate‐risk pulmonary embolism, and large randomized trials aiming to validate their efficacy, safety, and prognostic impact are about to start.

Venous thromboembolism (VTE), clinically presenting as deep vein thrombosis (DVT) or acute pulmonary embolism (PE), is the third most frequent acute cardiovascular syndrome after myocardial infarction and stroke. 1 The incidence of VTE is almost eight times higher in individuals aged ≥80 years than in the fifth decade of life, 2 and thus, as societies age worldwide, annual VTE incidence rates continue to increase over time. 3, 4 Recently, an analysis of vital registration data from the World Health Organization (WHO) Mortality Database investigated the trends in annual PE-related mortality in the WHO European Region (including Central Asia), with a total population of ≈651 million. 5 Although the overall age-standardized PE-related annual mortality rate decreased from 12.7 to 6.5 deaths per 100 000 population between 2000 and 2015, PE-related mortality continues to exceed 80 deaths per 100 000 population among the elderly in many countries. 5 A further study analyzing the trends in North America revealed, for the first time, a "rebound" increase in PE-related mortality among young and middle-aged adults in the United States since 2006. 6 These facts illustrate the magnitude of the burden and multitude of challenges that, in spite of the recent advances in the prevention and treatment of thrombosis, VTE will continue to impose on populations and health care systems worldwide in the years to come.

This article reviews the current standard of care following a decade of revolution in anticoagulation, and outlines the most promising fields of ongoing research and the populations most likely to benefit from emerging antithrombotic agents and strategies in the decade to come.

For many decades and until very recently, 7, 8 the standard approach to initiating anticoagulation treatment in a patient with acute VTE consisted of parenteral (subcutaneous) weight-adjusted lowmolecular-weight heparin (LMWH) 9 or fondaparinux 10 administration; (intravenous) unfractionated heparin (UFH) infusion is now mainly reserved for patients presenting with hemodynamic compromise or severely reduced renal function. 11 In parallel with parenteral treatment, oral anticoagulation needs to start as soon as it is safe and feasible to do so. For over half a century, oral treatment of VTE has been synonymous with coumarin anticoagulants, that is, vitamin K antagonists (VKAs), which inhibit vitamin K epoxide reductase and thus impair the biosynthesis of functional (carboxylated) coagulation factors II, VII, IX and X (as well as two anticoagulant factors, protein C and protein S) in the liver. 12 In view of the slow onset of action of VKAs, which do not affect factors already present in the circulation, parallel administration of LMWH, fondaparinux, or UFH needs to be continued for at least 5 days and until the international normalized ratio value has been in the therapeutic range of 2.0-3.0 for 2 consecutive days.

VKAs are effective drugs, but they have a narrow therapeutic window and exhibit substantial variations in bioavailability and in interpatient as well as intrapatient dose requirement, 13 and need routine laboratory monitoring. These challenges, along with a multitude of drug-drug interactions and, in association with all the above, a persistently elevated risk for major, potentially life-threatening bleeding during chronic administration, 14, 15 have limited the use of these drugs and thus the implementation of long-term secondary prevention after an index episode of VTE in clinical practice. 16 The direct oral anticoagulants (DOACs) were developed and approved in the past decade with the aim to overcome these weaknesses and deficits. DOACs are small molecules that, in contrast to UFH, LMWH, fondaparinux, and the VKAs, inhibit directly a single activated coagulation factor; the target is thrombin for dabigatran, and activated factor X (FXa) for apixaban, edoxaban, rivaroxaban, and betrixaban (the latter drug is approved for VTE prophylaxis in the United States). In view of their predictable bioavailability and pharmacokinetics, DOACs can be given at fixed doses without routine laboratory monitoring, a practical advantage compared to treatment with a VKA. 17 The doses, regimens, and duration of treatment tested in the phase 3 trials of DOACs for the treatment and secondary prophylaxis of VTE are summarized, along with the main efficacy and safety results of these trials, in Table 1 . Meta-analyses have confirmed the noninferiority of DOACs compared to the combination of LMWH with a VKA for prevention of symptomatic or lethal VTE recurrence, along with significantly reduced rates of major, lifethreatening bleeding 18 ; these safety data are supported by "realworld" evidence. 15, 19 In addition, DOACs have been successfully tested as part of a single-oral-drug anticoagulation strategy, which helps to avoid, in eligible, hemodynamically stable patients, the need for lead-in parenteral anticoagulation through the use of higher doses of apixaban over the first 7 days 20 or rivaroxaban over the first 3 weeks. 21, 22 Finally, administration of reduced-dose apixaban or rivaroxaban for extended treatment and secondary prevention of VTE (after 6 months of therapeutic anticoagulation) may further improve the benefit-to-risk ratio of these DOACs over the long term. 23, 24 In view of all the above, the DOACs currently represent the standard of care in the treatment and secondary prophylaxis of VTE, having displaced not only the VKAs but also, at least in part, the LMWH in the general population and in selected patients with cancer. 11,25-28

Based on the efficacy and particularly the very good safety profile of the DOACs, as demonstrated by the large trials summarized in Table 1 , current guidelines 11, 25 recommend to consider an extended secondary prevention of indefinite duration in the majority of patients after a first episode of VTE. Apart from patients who have suffered multiple episodes of VTE, potential candidates include also those with no identifiable risk factor for the index event (so-called unprovoked VTE), patients with a persistent risk factor including cancer, and those with a weak transient or reversible risk factor such as long-haul travel. However, it needs to be borne in mind that patients at high bleeding risk as based on the investigators' judgement, medical history, or chemical laboratory parameters, were excluded from the extension studies with DOACs [22] [23] [24] 29 ; this had also been the case for studies on extended anticoagulation with VKAs. 30, 31 Although most likely less common than in the VKA era, life-threatening bleeding complications do occur among patients taking DOACs in everyday practice, 15, 19, 32 and we may witness an increase in their absolute numbers in the future, notably among patients with VTE who now receive lifelong secondary prophylaxis instead of the 3-month or 6-month treatment periods in the past.

This risk of bleeding in an aging population with thrombotic events may be related, among others, to a progressive decline in renal function. This caveat particularly applies to DOACs as small molecules that undergo, to a varying but in all cases significant extent, renal elimination. 17 In the phase 3 trials on VTE, and in contrast to those on stroke prevention in atrial fibrillation, the DOACs dabigatran, rivaroxaban, and apixaban were given at an unchanged (nonreduced) dose in patients with mild to moderate renal dysfunction (largely corresponding to an estimated glomerular filtration rate [eGFR] of 30-59 mL/min); only edoxaban was given at a dose reduced by 50% in this patient group. An eGFR < 25 mL/min was an exclusion criterion in the trials that tested apixaban, whereas for the trials investigating rivaroxaban, edoxaban, and dabigatran, the lowest acceptable eGFR was 30 mL/min. 11, 17 At the far end of the severity spectrum, patients with end-stage renal disease on hemodialysis are a particularly vulnerable group with a high thrombotic risk but at the same time also a high bleeding risk on anticoagulation. 33 Notwithstanding some encouraging preliminary data, [34] [35] [36] the DOACs have not been able to convincingly show a favorable risk-to-benefit clinical profile in this growing population.

Clinical trials 37 as well as ex vivo studies 38 conducted soon after DOAC approval, indicated that these drugs, by targeting a single specific coagulation factor downstream of the contact pathway (which is shown on the left side of Figure 1 ), may possess neither adequate efficacy nor acceptable safety for treatment of patients with mechanical heart valves. This limitation is also likely to apply to patients on extracorporeal membrane oxygenation circuits as well as those carrying left ventricular assist devices, the use of which is expected to increase in the next years as part of the management of severe heart failure. to VKAs, mostly thanks to their (more) predictable pharmacokinetics and stable anticoagulant effect. Nevertheless, bleeding does remain a concern with these drugs, 45 a fact that is to be expected in light of the central role of their target proteins for hemostasis.

Consequently, attention has turned to upstream components of the so-called contact system as possibly even safer targets, at least for particular patient groups and in particular clinical situations as outlined above. Most of the existing epidemiological and experimental data point to factor XI (FXI), 46 which is activated by activated factor XII (FXIIa) and maximizes thrombin generation via the intrinsic tenase complex activated factor IX-activated factor VIII without interfering with the interaction between factor VII and tissue factor ( Figure 1 ). The properties and main fields of investigation for inhibitors of the intrinsic coagulation pathway and more specifically of FXI, are displayed in Table 2 , the focus being on their potential clinical relevance to patients with VTE. The results of two already completed and published phase 2 clinical trials on VTE prophylaxis are summarized in Table 3 . and particularly offset of their effects. 46 Of these, the oral inhibitor BMS-986177, also known as JNJ-70033093, is currently being tested against enoxaparin in VTE prophylaxis in elective total knee arthroplasty, and in patients with end-stage renal disease on hemodialysis ( 

Although FXI is formally considered a component of the contact pathway and lies upstream of FX and thrombin, it is activated by thrombin, having been formed via the extrinsic pathway (following activation of factor VII [FVIIa] by tissue factor), and plays in turn an important role on amplifying thrombin generation ( Figure 1 ).

Consequently, FXI does play a relevant role in the physiology of hemostasis, and it is not surprising that its inhibition by the most effective dose of the monoclonal antibody osocimab in a phase 2 study was associated with a bleeding frequency comparable to that of enoxaparin and higher than that of apixaban 53 (Table 3 ). In con- Polyphosphates, including DNA and RNA released from injured or dying cells or neutrophil extracellular traps, are increasingly attracting attention as activators of the contact system ( Figure 1) and key mediators of immunothrombosis. 56 67 ), but clinical testing was terminated due to lack of efficacy or because of safety concerns.

Aspirin may have antithrombotic properties beyond classical inhibition of platelet aggregation, 68 and it was reported to exert moderate protective effects against VTE recurrence. 69,70 However, aspirin is inferior to standard anticoagulant treatment for secondary VTE prevention, 23 and its use may thus be considered only in the rare case of a patient who refuses to take or is unable to tolerate any form or oral anticoagulation. 11 Dose-dependent tissue factor inhibition 71 may contribute, along with thrombomodulin activation 72 and stimulation of antiinflammatory mechanisms, 73 to the antithrombotic effects of statins, and the impact of these drugs on the coagulation system may be independent, at least in part, from their lipid-lowering effects. 74 Although the use of statins has been associated with a lower incidence of first and recurrent VTE, 75 

Beyond anticoagulation, which is the standard of care for all patients with VTE regardless of clinical presentation and severity, 

VTE prophylaxis in ESRD on hemodialysis (NCT04523220, ongoing)

Abbreviations: CYP, cytochrome P450; ESRD, end-stage renal disease; FXI, factor XI; FXIa, activated factor XI; FXIIa, activated factor XII; TKA, total knee arthroplasty; VTE, venous thromboembolism. The first-in-human study of ONO-7684 was also reported. ONO-7684 is an oral small-molecule FXIa inhibitor, which was assessed in a phase 1 randomized double-blind placebo-controlled study on healthy individuals. It demonstrated good tolerability with mild adverse effects, a half-life of 22-28 hours, and peak concentrations that increased with food intake. 99 The safety, pharmacokinetics, and pharmacodynamics of BAY-2433334 were also evaluated in a phase 1 study on healthy men, reporting good tolerability and safety, a half-life of around 15 hours, and a decrease in peak concentrations by food intake. 100

In the past decade, new oral drugs directly targeting coagulation factor Xa or thrombin revolutionized the treatment of thrombotic diseases including VTE. Nevertheless, in a continuously growing population of possible candidates for long-term anticoagulation, safety concerns and unmet needs persist in the treatment of vulnerable patient groups, related, for example, to severely reduced renal function, implantable heart valves or assist devices, and extracorporeal support of the circulation. Attention has turned to components upstream of the final common pathway, with epidemiological and experimental data pointing to FXI as a promising target. Of the numerous approaches proposed for FXI inhibition, second-generation antisense oligonucleotides, several humanized monoclonal antibodies, and a F I G U R E 2 Graphical overview of the main types of available reperfusion strategies and techniques for acute pulmonary embolism TA B L E 4 Technologies for catheter-directed treatment (adapted from Hobohm et al. 109 and Valerio et al. 80 )

Catheter-directed thrombolysis

The catheter is inserted directly into the pulmonary artery and the thrombolytic agent released close to the location of the thrombus. 

Catheter-directed embolectomy, rheolytic

High-pressure jet streams disrupt the thrombus, which is then trapped in a low-pressure zone and aspirated in the catheter.

Observational studies

The thrombus is aspirated via a pump, reintroducing excess aspirated blood via a venovenous bypass system or with mechanical clot engagement. impact are about to start. The revolution that swept antithrombosis in the 2010s will most likely be followed by a phase of targeted evolution in the decade to come; although less spectacular, this phase will be at least as interesting and relevant.

The authors thank Ms Beck Katja from the Department of Graphic,

Center of the Johannes Gutenberg University, Mainz for the design of Figure 1 .

AM, SB and SK designed the paper, critically reviewed the literature and reviewed and edited the final manuscript. 

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