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Advances in Antithrombotic Therapy

Originally published, Thrombosis, and Vascular Biology. 2019;39:7–12


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.

Thrombosis is responsible for 1 in 4 deaths worldwide. Thrombosis can occur in arteries or veins. On the arterial side, thrombosis is the most common underlying cause of myocardial infarction (MI), ischemic stroke, and acute limb ischemia, whereas on the venous side, it causes deep-vein thrombosis and pulmonary embolism, collectively known as venous thromboembolism (VTE). Together, these disorders are responsible for an estimated 10 million deaths each year.1 Therefore, thrombosis is a major healthcare problem.

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All thrombi consist of aggregated platelets, fibrin, and trapped blood cells, but the proportion of these components differs between arterial and venous thrombi. Platelets predominate in arterial thrombi, which form under high shear conditions, whereas fibrin is the major component of venous thrombi because they form where blood flow is reduced. These differences inform therapy. Thus, antiplatelet therapy is the current cornerstone for prevention and treatment of arterial thrombosis, whereas anticoagulants are the mainstay for VTE.

Bleeding is the major side effect of antithrombotic therapy. The risk of major bleeding is ≈1.8-fold higher with dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel than with aspirin alone.2 Likewise, the risk of bleeding increases at least 2-fold when aspirin is used in combination with an anticoagulant.3 Although the direct oral anticoagulants (DOACs), which include dabigatran, apixaban, edoxaban, and rivaroxaban, are associated with less major bleeding than vitamin K antagonists such as warfarin, the risk of bleeding almost doubles when the DOACs are administered in combination with aspirin.4–7 Therefore, there remains a need for safer anticoagulant therapy.

Addressing gaps in thrombosis management, this article focuses on 2 recent advances. The first is the evidence that addition of low-dose rivaroxaban to aspirin is superior to aspirin alone for secondary prevention of atherothrombosis in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD); a benefit that comes at the cost of more bleeding. Addressing the problem of bleeding, the second advance relates to development of FXI (factor XI) inhibitors as potentially safer anticoagulants.

Addition of Low-Dose Rivaroxaban to Aspirin

Despite single or DAPT, up to 11% of patients with the acute coronary syndrome and 5% of patients with stable CAD or PAD have recurrent ischemic events each year.8,9 The failure of antiplatelet therapy suggests the presence of triggers that are unresponsive to platelet suppression. Thrombin is the likely culprit because its generation is initiated by tissue factor exposed at sites of atherosclerotic plaque disruption. In addition to converting fibrinogen to fibrin, thrombin is a potent platelet agonist and activated platelets provide a surface for the assembly of clotting factor complexes that enhance thrombin generation by >1000-fold. Therefore, suppression of thrombin generation and platelet activation may be better than antiplatelet therapy alone to prevent atherothrombosis.

The importance of thrombin as a driver of atherothrombosis is supported by the observation that markers of thrombin generation, such as thrombin-antithrombin complexes and prothrombin fragment 1.2, remain elevated for more than a year after MI.10,11 These findings explain why compared with aspirin alone after MI, the combination of warfarin plus aspirin reduced the annual rate of recurrent MI by 44% and the annual rates of stroke and revascularization by 54% and 20%, respectively.3 However, these benefits were offset by a 2.5-fold increase in the incidence of major bleeding.3 Consequently, warfarin is rarely used for this indication.

To be effective, warfarin must be dose adjusted to achieve an international normalized ratio >2. Thus, reduced intensity warfarin (target international normalized ratio 1.5–2) was not only less effective than usual intensity warfarin (target international normalized ratio 2–3) but failed to reduce the risk of bleeding.12 Unlike warfarin, low-dose regimens of DOACs are effective, and seem to be associated with less bleeding than higher dose regimens, thereby providing a safer anticoagulant platform when used in combination with antiplatelet therapy.13 Supporting this concept, the addition of low-dose rivaroxaban (2.5 mg twice daily) on top of DAPT reduced major adverse cardiac events by 16% in stabilized patients with the acute coronary syndrome in the ATLAS-ACS-2 TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome 2–Thrombolysis in Myocardial Infarction 51).14 Despite a 3-fold increase in bleeding, rivaroxaban plus DAPT reduced mortality compared with DAPT alone consistent with a net clinical benefit. When used on top of antiplatelet therapy, dosing of oral FXa inhibitors is critical because a higher dose of rivaroxaban (5 mg twice daily) in the ATLAS-ACS-2 TIMI 51 trial or full-dose apixaban (5 mg twice daily) in the APPRAISE-2 trial (Apixaban for Prevention of Acute Ischemic Events 2) increased bleeding without enhancing efficacy.14,15 Therefore, when used in conjunction with antiplatelet therapy, lower doses of oral FXa inhibitors seem to be better than higher doses.

Despite single antiplatelet therapy with aspirin or clopidogrel, up to 5% of patients with chronic atherothrombosis have recurrent ischemic events each year.9 In the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), 27 395 patients with stable CAD or PAD were randomized to 1 of 3 treatments arms: rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily; rivaroxaban 5 mg twice daily alone; or aspirin 100 mg once daily.16 About 90% of participants had CAD and 27% had PAD. The primary outcome, a composite of cardiovascular death, stroke, or nonfatal MI, was significantly lower with rivaroxaban plus aspirin than with aspirin alone (4.1% and 5.4%, respectively; hazard ratio [HR], 0.76; 95% CI, 0.66–0.86; P<0.001). This translates to an absolute risk reduction of 1.3%, a relative risk reduction of 24% and a number needed to treat of 76. The primary outcome was not significantly lower with rivaroxaban alone than with aspirin (4.9% and 5.4%, respectively; HR, 0.90; 95% CI, 0.79–1.03; P=0.12). All-cause mortality was reduced by 0.7% with the rivaroxaban plus aspirin combination compared with aspirin alone (HR, 0.82; 95% CI, 0.71–0.96; P=0.01). The rate of major bleeding was significantly higher in the rivaroxaban plus aspirin group than in the aspirin alone group (3.1% and 1.9%; respectively; HR, 1.70; 95% CI, 1.40–2.05; P<0.001). Most of the excess bleeds were in the gastrointestinal tract. Although there were numerically more hemorrhagic strokes (0.2% versus 0.1%) and fatal bleeds (0.2% versus 0.1%) with the combination regimen than with aspirin alone, such events were infrequent, and the differences were not statistically significant. The rate of the net clinical benefit, the composite of cardiovascular death, stroke, MI, fatal, or symptomatic bleeding into a critical organ, was 4.7% in the rivaroxaban plus aspirin group and 5.9% in the aspirin alone group (HR, 0.80; 95% CI, 0.70–0.91; P<0.001). Therefore, the combination of low-dose rivaroxaban and aspirin has a clear net benefit for prevention of recurrent ischemic events compared with aspirin alone. Nonetheless, the increase in bleeding that occurs when rivaroxaban is added on top of aspirin opens the door to anticoagulant strategies that provide a safer platform for use with antiplatelet agents.

Safer Anticoagulant Strategies

The goal of anticoagulation therapy is to attenuate thrombosis without perturbing hemostasis. Although the DOACs come closer to this goal than vitamin K antagonists, bleeding is not eliminated with the DOACs. Thus, the annual rate of major bleeding with DOACs in patients with atrial fibrillation ranges from 2% to 3%, while the annual rate of intracranial bleeding ranges from 0.3% to 0.5%.17 This is problematic, because the fear of bleeding prompts the underuse of anticoagulant thromboprophylaxis in over one-third of atrial fibrillation patients, and among those given DOACs, up to 50% are inappropriately treated with the lower dose regimens.18,19 Therefore, safer anticoagulants are needed.

The DOACs inhibit FXa or thrombin, downstream enzymes in the coagulation cascade. Interest has now shifted to FXII and FXI, which lie upstream to FXa and thrombin. This shift stems from the fact that basic and epidemiological studies suggest that FXII and FXI are important in thrombosis yet FXII has no role in hemostasis and spontaneous bleeding is rare with congenital FXI deficiency. Therefore, FXII and FXI are important for thrombosis but less so for hemostasis.20–22 Consequently, FXII and FXI are promising targets for development of safer anticoagulants.

Role of FXII and FXI in Thrombosis

Several lines of evidence suggest that FXII and FXI are essential for thrombus stabilization and growth but are dispensable for hemostasis. This phenomenon can be explained by the positive feedback amplification loop that occurs when FXI is activated by FXIIa or thrombin and by the subsequent augmented activation of thrombin activatable fibrinolysis inhibitor, which attenuates fibrin clot degradation (Figure).23 However, tail bleeding in mice deficient in FXII or FXI is indistinguishable from that in wild-type mice consistent with the potentially dispensable role of these coagulation factors in hemostasis. Furthermore, patients with FXII deficiency do not bleed, whereas those with FXI deficiency rarely experience spontaneous bleeding but can bleed after trauma or surgery particularly in tissues rich in fibrinolytic activity, such as the nasopharyngeal, gastrointestinal, or genitourinary tracts. Therefore, FXII and FXI are important for thrombosis but not for hemostasis.


Figure. Role of FXII (factor XII) and FXI in thrombosis. Activation of FXI by FXIIa or thrombin is essential for thrombus growth and stabilization. Activation of FXI promotes thrombin generation via intrinsic tenase and prothrombinase. Thrombin not only triggers clot formation but also promotes clotting by attenuating fibrinolysis through activation of thrombin activatable fibrinolysis inhibitor (TAFI). Therefore, inhibition of FXI or FXII is expected to suppress thrombin generation, thereby attenuating both fibrin formation and TAFI activation. Attenuated fibrin formation results in smaller clots and without TAFI activation, there is no brake on fibrinolysis.

Studies in animals support the role of FXII and FXI in thrombosis.24,25 FXII- or FXI-deficient mice are protected from ischemic stroke and thrombi formed after venous flow restriction are smaller than those in wild-type mice.26 In a rabbit model, FXII or FXI knockdown with specific antisense oligonucleotides (ASOs) reduced catheter thrombosis.27 Likewise, FXI knockdown in baboons attenuated arteriovenous shunt thrombosis in a concentration-dependent manner once FXI levels decreased <50% of normal.28 In this model, however, antibodies against FXI attenuated platelet and fibrin deposition more than those directed against FXII.29,30 Therefore, FXI seems to be a more important driver of thrombosis than FXII in nonhuman primate models.

Strategies to Inhibit FXI

Several strategies for FXI inhibition are under investigation (Table 1). These include (1) ASOs that reduce hepatic synthesis of FXI,27,28,31 (2) monoclonal antibodies that block FXI activation or FXIa activity,32 (3) aptamers that bind FXI or FXIa,33,34 and (4) small molecules that block the active site of FXIa,35–38 or induce allosteric modulation.39,40 ASOs, antibodies, and aptamers require parenteral administration, whereas small molecule active site inhibitors have the potential for parenteral or oral delivery. It takes 3 to 4 weeks of ASO treatment to lower FXI levels into the therapeutic range, which limits its utility for acute therapy. In contrast, antibodies, aptamers, and small molecules have a rapid onset of action. The long half-life of FXI-directed antibodies or ASOs could be problematic if there is bleeding with trauma or surgery. Therefore, each strategy has strengths and weaknesses for clinical development.

Table 1. Strategies to Inhibit FXI

FXI Inhibitor ClassCompoundsMechanisms of Action
Antisense oligonucleotideIONIS-416858Reduce hepatic synthesis of FXI by inducing catalytic degradation of FXI mRNA.
Monoclonal antibodiesBAY1213790, BAY1831865, and MAA868Suppress FXIa generation and/or inhibit FXIa activity.
Small peptidomimetic moleculesBMS986177, EP-7041, and ONO-5450598Bind reversibly to the catalytic domain of FXIa and inhibit its activity.
Aptamers11.16, 12.7, and FXI inhibitory aptamerBind to FXI and FXIa and block its activity.

FXI indicates factor XI.

Clinical Trials

The first agent tested in humans was the FXI-directed ASO (IONIS-416858), which is given subcutaneously. In healthy volunteers, IONIS-416858 reduced FXI antigen and activity levels in a concentration-dependent manner.41 A phase 2 study in patients undergoing elective knee replacement randomized 300 patients to receive either subcutaneous IONIS-416858 (at doses of 200 or 300 mg starting 35 days before surgery) or enoxaparin (40 mg once daily with the first dose given 12 hours before or after surgery).42 Both treatments were continued for at least 10 days at which point bilateral venography was performed. The primary efficacy outcome was VTE, which included the composite of asymptomatic deep-vein thrombosis, symptomatic deep-vein thrombosis or pulmonary embolism and VTE-related mortality, while the principal safety outcome was the composite of major and clinically relevant nonmajor bleeding. The primary efficacy outcome occurred in 36 of 134 patients (27%) and in 3 of 71 patients (4%) who received the 200 and 300 mg doses of IONIS-416858, respectively, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200 mg IONIS-416858 regimen was noninferior, and the 300 mg ASO regimen was superior to enoxaparin (P<0.001). The rates of bleeding were 3% in both IONIS-416858 groups and 8% in the enoxaparin groups; differences that were not statistically significant. Therefore, lowering FXI levels reduces postoperative VTE more than enoxaparin without increasing the risk of bleeding. Larger phase 3 trials are needed to confirm that targeting FXI enhances the benefit-risk profile compared with currently available anticoagulants.

Other phase 2 trials are planned or underway (Table 2). The efficacy and safety of BAY 1213790, a monoclonal antibody that inhibits FXIa, are being compared with those of enoxaparin and apixaban (URL: Unique identifier: NCT03276143). The study is conducted in 2 parts. In the first part, BAY 1213790 is administered postoperatively, while in the second part, 2 doses of BAY 1213790 selected from part 1 are being evaluated with preoperative administration. As per their labels, enoxaparin and apixaban are started postoperatively, although a preoperative dose of enoxaparin is allowed. The results of the study have not yet been disclosed.

Table 2. Phase 2 Studies of FXI Inhibitors study ID; Sample sizeDesignPopulationInterventionsComparatorsEfficacy and Safety Outcomes
FXI-ASO (IONIS-416858)NCT01713361*; N=300Randomized, open label, active comparator.Patients undergoing elective total knee arthroplasty.FXI-ASO 200 mg or 300 mg SC dosing regimens starting 36 days before surgery with last dose 3 days after surgery.Enoxaparin 40 mg SC in the evening of surgery for at least 8 days postoperatively.Composite of asymptomatic DVT, symptomatic VTE, and unexplained death. Clinically relevant bleeding.
BAY1213790NCT03276143; N=813Randomized, open label, active comparator.Patients undergoing elective total knee arthroplasty.BAY1213790. Part 1: single infusion in morning postsurgery. Part 2: single infusion in the evening of surgery.Enoxaparin or apixaban for at least 10 days.Composite of asymptomatic DVT, symptomatic VTE, and unexplained death. Clinically relevant bleeding.
FXI-ASO (IONIS-416858)NCT02553889; N=49Randomized, double-blind, placebo-controlled trial.Patients with end-stage renal disease on hemodialysis.FXI-ASO 200 mg or 300 mg SC given twice a week for first 2 wks, then weekly for 10 wk.PlaceboFXI level, aPTT, PT. Bleeding events. Extent of clotting in the air trap and on the dialysis membrane.
FXI-ASO (IONIS-416858)NCT03358030§; N=204Randomized, double-blind, placebo-controlled trial.Patients with end-stage renal disease on hemodialysis.Three dose cohorts in which patients receive weekly SC treatment for 26 wk.PlaceboTreatment-emergent adverse effect, bleeding, trough level of drug, changes in FXI antigen and activity, clotting on dialysis membrane and circuit.

aPTT indicates activate partial thromboplastin time; ASO, antisense oligonucleotides; DVT, deep-vein thrombosis; FXI, factor XI; SC, subcutaneous; and VTE, venous thromboembolism.

*Factor XI ASO for prevention of VTE.

†A randomized, active-comparator-controlled, multicenter study to assess the safety and efficacy of different doses of BAY1213790 for the Prevention of Venous Thromboembolism in Patients Undergoing Elective Primary Total Knee Arthroplasty, Open-label to Treatment and Observer-blinded to BAY1213790 Doses (FOXTROT).

‡A study of Safety, PK, and PD of ISIS-416858 administered subcutaneously to patients with end-stage renal disease on hemodialysis.

§A study of ISIS-416858 administered subcutaneously to patients with end-stage renal disease on hemodialysis.

Two phase 2 studies are evaluating the safety of IONIS-416858 in patients on chronic hemodialysis (URL: Unique identifiers: NCT02553889 and NCT03358030). Despite the use of heparin during dialysis, preliminary data suggest that compared with placebo, lowering FXI levels in such patients reduces clotting in the air trap and on the dialysis membrane. Finally, a phase 2 study will soon start in patients with high-risk transient ischemic attack or small ischemic stroke. The study will evaluate BMS986177, an oral FXIa inhibitor, versus placebo on top of clopidogrel plus aspirin for 21 days followed by aspirin alone thereafter. Evidence of new stroke or intracranial bleeding on repeated brain imaging will be the primary efficacy and safety outcomes, respectively. Therefore, clinical trials with FXI inhibitors are well underway.

Conclusions and Future Directions

Advances in our understanding of the role of thrombin in atherothrombosis and the capacity to inhibit its generation with low-dose rivaroxaban will revolutionize secondary prevention in CAD or PAD. The challenge will be identifying high-risk patients who will benefit most from combined treatment with rivaroxaban plus aspirin. Such patients are likely to be those with polyvascular bed involvement, symptomatic PAD, and renal impairment.

Although the DOACs have raised the bar for anticoagulation therapy, bleeding remains a concern. Strategies targeting FXI may prove to be safer than inhibitors of FXa or thrombin because there is mounting evidence that FXI is important for thrombus stabilization and growth but less so for hemostasis. Phase 3 trials with these agents will need to focus on unmet medical needs, particularly those where current therapies are limited in both efficacy and safety. These could include prevention of cardiovascular events in patients with chronic kidney disease, stroke prevention in atrial fibrillation patients at high risk for bleeding, such as those with the end-stage renal disease who are on hemodialysis, and secondary prevention after ischemic stroke. Prevention of clotting on medical devices, such as central venous catheters, mechanical heart valves, and left ventricular assist devices, is another possibility. The clinical potential of FXI-directed anticoagulant strategies represents an exciting new era in anticoagulation that should reduce the risk of bleeding without compromising efficacy.

Nonstandard Abbreviations and Acronyms


antisense oligonucleotide


coronary artery disease


dual antiplatelet therapy


direct oral anticoagulant


factor XI


hazard ratio


myocardial infarction


peripheral artery disease


venous thromboembolism


N.C. Chan holds a McMaster University, Department of Medicine Internal Research Career Award. J.I. Weitz holds the Canada Research Chair (Tier 1) in Thrombosis and the Heart and Stroke Foundation/J.F. Mustard Chair in Cardiovascular Research at McMaster University.


Correspondence to Jeffrey Weitz, MD, Thrombosis and Atherosclerosis Research Institute, McMaster University, 237 Barton St E, Hamilton, ON L8L 2X2, Canada. Email


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