Perspectives: Direct and specific inhibition of factor Xa: an emerging therapeutic strategy for atherothrombotic disease

Abstract

Cardiovascular (CV) disease and its clinical manifestations are major causes of morbidity and mortality worldwide. Acute coronary syndromes (ACS) are the most common emergent manifestation of CV disease, occurring in 1 190 000 patients annually in the USA.¹ Improvements in the diagnosis and treatment of ACS have led to the reduction in the rates of ST-elevation myocardial infarction (STEMI), and now non-ST-elevation ACS (NSTE-ACS) subsequently accounts for 77% of all acute infarcts.² Despite optimal medical therapy, including double antiplatelet therapy (DAPT) with the newer and more potent P2Y12 receptor inhibitors, and high-dose statin treatment, the residual risk of reinfarction only decreases by 30%, which means that 70% of events are not prevented,³ a still unacceptable rate. Thus, new strategies to reduce ACS risk are urgently needed.

Acute coronary syndrome is usually the result of atherosclerotic plaque rupture. Coronary plaques vulnerable to rupture are characterized by a lipid-laden necrotic core in which macrophage infiltration leads to the release of matrix metalloproteinases and inflammatory cytokines. This initiates a vicious inflammatory process, which involves thinning of the fibrous cap that culminates in plaque rupture and the exposure of tissue factor with the consequent activation of factor X.⁴ Active factor X (Xa) subsequently stimulates the conversion of the inactive prothrombin to the active serine protease, thrombin. Thrombin is one of the most potent agonist for platelet aggregation, and it also catalyses the conversion of soluble fibrinogen to insoluble strands of fibrin, leading to thrombus formation and coronary occlusion.⁵ This suggests a potential opportunity for reducing residual risk of ACS through direct thrombin inhibition or factor Xa inhibition.

Interestingly, thrombin generation remains elevated up to 6 months after an ACS episode.⁶ Specifically, these initial 6 months post-ACS is when most of the recurrent events take place according to GUSTO Registry ACS.⁷ Therefore, inhibition of thrombin generation seems a rational therapeutic target in the treatment of ACS. Two major observations support the notion that a more effective antithrombotic therapy may reduce recurrent ACS events: (i) a meta-analysis of 10 trials and 5938 patients showed a 44% reduction in recurrent myocardial infarction (MI) by warfarin (which also reduces Xa) + ASA when compared with ASA monotherapy;⁸ (ii) fondaparinux, an indirect Xa inhibitor, has also showed benefits in the treatment of ACS^9,10 (although these studies only included acute administration of fondaparinux).

Oral Xa inhibitors are novel anticoagulants overcoming many of the disadvantages of warfarin (numerous food and drug interactions, narrow therapeutic window, variable dose–response relationship, need for frequent monitoring), thus offering a new treatment strategy in patients with ACS. In the present article, we review the current evidence for the addition of novel Xa inhibitors to antiplatelet therapy in the context of ACS.

Otamixaban

The synthetic intravenous direct factor Xa inhibitor, otamixaban, has shown to inhibit thrombin generation in a dose-dependent manner, with a rapid onset and offset of action, linear kinetics, and limited renal elimination.¹¹ The dose-ranging SEPIA-ACS1 TIMI 42 trial involved NSTEACS patients and a planned invasive strategy. Even though not powered for efficacy, the trial showed a reduction in the combined outcome of death or MI in the otamixaban group when compared with unfractioned heparin (UFH) plus eptifibatide and similar bleeding rates with otamixaban at mid-range doses.¹²

Given its rapid onset and offset, intravenous administration, and predictable anticoagulant response not requiring monitoring, otamixaban was attractive as a single anticoagulant to be used in ACS. The TAO trial¹³ was designed as a superiority trial to compare the clinical efficacy and safety of otamixaban with that of UFH plus eptifibatide in 13 229 NSTEACS patients. Otamixaban was not superior to UFH + eptifibatide neither in primary efficacy outcome [composite of all-cause death or new MI, RR 0.99 (95% confidence interval, 0.85–1.16); P = 0.93];¹³ besides, the rate of bleeding (the primary safety outcome) was increased by otamixaban [RR 2.13 (1.63–2.78); P < 0.001]. Therefore, these findings do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early percutaneous coronary intervention (PCI).

Darexaban

Darexaban is a pro-drug rapidly absorbed in the stomach and quickly converted to its active metabolite darexaban glucuronide.¹⁴ Unlike other direct factor Xa inhibitors, darexaban does not interact with CYP3A4/P-glycoprotein inhibitors and inducers.¹⁴ The benefit of darexaban has been demonstrated in the prevention of venous thromboembolism and in the prevention of stroke in non-valvular AF (in the Phase II OPAL-2 trial).¹⁵

The role of darexaban in the treatment of ACS was examined in the Phase II dose finding and safety trail, RUBY-1.¹⁶ Darexaban showed a significant dose-dependent increase in bleeding. Darexaban clinical development has been for the moment.

Apixaban

Apixaban is an orally available, direct-acting, reversible, and highly selective factor Xa inhibitor. Part of the drug is metabolized by CYP enzymes, thus it is susceptible to interaction with CYP enzyme inducers and inhibitors. As it partially undergoes renal excretion, apixaban is not recommended in patients with end-stage renal failure (creatinine clearance < 15 mL/min), and it can be used with caution with severe renal failure (creatinine clearance 15–30 mL/min).¹⁷ Dose modification is not needed in the elderly.

Apixaban has been shown to reduce the incidence of venous thromboembolism in patients undergoing orthopaedic surgery and to prevent thromboembolic events in patients with non-valvular AF.¹⁸ The role of apixaban in ACS was first examined in the APPRAISE, a Phase II dose-escalation study,¹⁹ in which 1715 patients after ACS were randomized to 6 months of placebo or apixaban (at one of the following doses: 2.5 mg twice daily, 10 mg once daily, 10 mg twice daily, or 20 mg once daily) on the top of aspirin (with or without clopidogrel). The two highest dose regimens of apixaban were discontinued early because of an unacceptable increase in total bleeding. Compared with placebo, apixaban was associated with a higher risk of major or clinically relevant non-major bleeding (2.5 mg twice daily, 5.7%; 10 mg once daily, 7.9%; placebo, 3.0%). Apixaban 2.5 mg twice daily [hazard ratio (HR) 0.73 (0.44–1.19), P = 0.21] resulted in lower rates of ischaemic events compared with placebo, while there was a trend in the same direction with apixaban 10 mg once daily [HR 0.61 (0.0.35–1.04), P = 0.07]. These findings suggested that the addition of apixaban to DAPT may provide a modest benefit at a price of a substantial increase in clinically significant bleeding.

These findings led to the Phase III APPRAISE II trial.²⁰ The study was terminated prematurely due to increased bleeding. In a total population of 7392 patients followed for a median of 8 months, apixaban failed to reduce the primary endpoint of MI, ischaemic stroke, or CV death [13.2 events per 100 patient-years vs. 14.0 events per 100 patient years, HR 0.95 (0.80–1.11), P = 0.51], irrespective of whether patients were receiving DAPT or aspirin alone and regardless of whether patients were managed conservatively or with revascularization. Apixaban increased TIMI major bleeding, the primary safety outcome [2.4 events per 100 patient-years vs. 0.9 events per 100 patient-years, HR 2.59 (1.50–4.46), P = 0.001]. Therefore, the addition of apixaban 5 mg twice daily, to antiplatelet therapy after ACS increased major bleeding without a significant reduction in ischaemic events.

Rivaroxaban

Rivaroxaban is another highly selective, reversible, oral direct factor Xa inhibitor capable of inhibiting both free factor Xa and factor Xa bound in the prothrombinase complex. It can be administered once daily,¹⁷ a great improvement for patient compliance. Rivaroxaban is not recommended in patients with creatinine clearance (CrCl) < 15 mL/min and it should be used with caution in patients with CrCl 15–29 mL/min. Rivaroxaban is metabolized via CYP3A4 enzymes, thus the concomitant use of potent CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's Wort), CYP3A4 inhibitors (ketoconazole, itraconazole), or HIV protease inhibitors (ritonavir) should be avoided.

Rivaroxaban is effective in the prevention and treatment of venous thromboembolism. In patients with non-valvular AF, rivaroxaban was non-inferior to warfarin in the prevention of stroke and systemic embolism.^21,22

The ATLAS ACS-TIMI 46 trial was a dose-finding Phase II study which evaluated rivaroxaban in ACS²³ in patients receiving aspirin alone (stratum 1) or DAPT (stratum 2). Rivaroxaban was associated with dose-dependent increased bleeding in both stratum 1 and 2, with absolute rates of bleeding being lower in patients receiving aspirin alone vs. DAPT. There was a non-significant reduction in primary efficacy events (death, MI, stroke, severe recurrent ischaemia requiring revascularization: 5.6 vs. 7.0% for placebo, HR 0.79; P = 0.10). Interestingly, ribaroxaban significantly reduced primary efficacy endpoint events in patients receiving aspirin alone [stratum 1; HR 0.53 (0.33–0.84)] or when revascularization was excluded from the analysis (P = 0.027).

These results led to the ATLAS ACS-TIMI 51 Phase III trial,²⁴ evaluating in 15 526 ACS patients the efficacy and safety of rivaroxaban (twice daily doses of either 2.5 or 5 mg) plus aspirin vs. aspirin alone, stratified by P2Y12 antagonists. As the primary evaluation strategy was based on a modified intention-to-treat analysis of data combined across both strata (i.e. all strata), the primary results are that rivaroxaban reduced the composite primary end-point (CV death, MI, and stroke) at both doses [whole rivaroxaban group HR 0.84 (0.74–0.96), P = 0.008], at the cost of increased TIMI major bleeding. Subgroup analysis demonstrated that the 2.5 mg twice daily reduced the risk of CV death [2.7 vs. 4.1%; HR 0.66 (0.51–0.86), P = 0.002] as well as death from any cause [2.9 vs. 4.5%; HR 0.68 (0.53–0.87), P = 0.002], whereas the 5 mg twice daily dose failed to do so. The twice-daily 2.5 mg dose resulted in fewer fatal bleeding events than the twice-daily 5 mg dose (0.1 vs. 0.4%, P = 0.04). When compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary artery bypass graft and intracranial haemorrhage, without a significant increase in fatal bleeding or other adverse events. Interestingly, rivaroxaban 2.5 mg reduced CV events in STEMI patients²⁵ (a benefit which persisted during treatment, irrespective of background antiplatelet therapies) and was also associated with a reduction in stent thrombosis.²⁶

Despite seemingly robust efficacy data, several key issues preclude our optimism. First and foremost, an unanticipated high rate of missing data, particularly the vital status of patients, precludes reliable and valid information.²⁷ Secondly, there was a lack of an expected dose–response, the 5 mg dose did not have greater efficacy compared with the 2.5 mg dose of rivaroxaban (establishment of dose or exposure response is an important consideration in regulatory decision-making). Thirdly, the impact of the two doses on the components of the primary composite endpoint is divergent, with a reduction in CV death (but not on MI) driving the treatment benefit with 2.5 mg, whereas the decrease in MI (but not CV death) driving benefit with the 5 mg dose. The degree to which missing data impacted overall interpretability of the trial results was the principal concern of this trial. It is usually considered that if the loss to follow-up rate exceeds the outcome event rate, results might be questionable; and if missing data are >20%, it poses a serious threat to the validity of the study (with missing data < 5%, the bias will be minimal). In the ATLAS ACS 2-TIMI 51 trial, the number of patients with unknown vital status (n = 1117) exceeded the total number of primary endpoint events (n = 1002) and the rate of missing data is 15.5%. An elegant article²⁷ explains how missing data can complicate interpretation or even invalidate an otherwise important study, and how as few as seven excess MACE are required to nullify the rivaroxaban efficacy in the ATLAS ACS-TIMI51 (seven events which may have happened among the missing data without the investigators detecting it). The missing data explain why the FDA has rejected the approval of rivaroxaban for ACS indication, even though the EMEA has granted a therapeutical indication for rivaroxaban 2.5 mg in patients with ACS.

Meta-analysis

As we have just reviewed, numerous prospective randomized placebo-controlled trials have been performed to evaluate the benefits of such an approach in patients after an ACS; however, the results are heterogeneous, and studies were commonly underpowered for separate outcomes. Therefore, systematic reviews and meta-analysis have been performed to gain more statistical power to study the clinical efficacy and safety of new anticoagulants vs. placebo in the setting of ACS.

In an initial meta-analysis²⁸ combining the seven randomized controlled trials (RCTs) with new anticoagulants (APPRAISE 1 and 2 for apixaban, ATLAS TIMI 46 and TIM 51 for rivaroxaban, RUBY for darexaban, REDEEM for dabigatran, and ESTEEM for ximelagatran), the authors show that the use of new-generation oral anticoagulant agents after ACS was associated with a dramatic increase in major bleeding events [odds ratio (OR) 3.03 (2.20–4.16), P = 0.001], and with significant but moderate reductions in the risk for stent thrombosis or ischaemic events [OR 0.86 (0.79–0.94), P = 0.001], without a significant effect on overall mortality [OR 0.9 (0.76–1.06), P = 0.22]. For the net clinical benefit, new-generation oral anticoagulant agents provided no advantage over placebo [OR 0.98 (0.90–1.06), P = 0.57]. These results have been recently confirmed by a second independent meta-analysis.²⁹

The most recent meta-analysis exclusively analyses the five RCTs performed with Xa inhibitors³⁰ and has also confirmed the previous results. There was no significant difference in mortality between patients treated with Xa inhibitors vs. those receiving the standard therapy [OR 0.97 (0.72–1.31), P = 0.86]. As shown in the previous meta-analyses, recurrent MI rates were decreased in the anti-Xa group [OR 0.86 (0.76–0.98), P = 0.02, number needed to treat = 189] at the expense of an increased risk of major bleedings [OR 3.24 (2.29–4.59), P = 0.001, number needed to harm = 104]. Therefore, the addition of the new oral anticoagulants on top of standard therapy seems to result in an excessive risk of major bleeding without any clear evidence of outweighting clinical benefits.

Unexplored issues with Xa inhibitors in acute coronary syndrome

Atrial fibrillation (AF) represents the most common arrhythmia. The average patient in recent AF trials3 and registries4 was ≥70 years of age,³¹ was mostly hypertensive (80%), and frequently had diabetes mellitus (33%), the three of them being know risk factors for atherothrombotic disease. The high incidence of CV risk factors and the increasing age of the population are the ideal ingredients for the presentation of both AF and ACS in the same patient. In fact, 30–40% of patients with AF have concomitant atherothrombotic vascular disease, and ≈10% of patients with an ACS or undergoing coronary stenting have concomitant AF.³¹ Current guidelines recommend DAPT after ACS (1 month for bare metal stents, 6–12 months for drug-eluting stents), while oral anticoagulation is the mainstay of treatment for AF patients at risk for stroke; subsequently, we are facing a patient with potential indication for triple antithrombotic therapy. Regarding triple therapy with warfarin, US guidelines recommend warfarin plus clopidogrel³² whereas European guidelines³³ suggest a triple combination of warfarin, aspirin, and clopidogrel for periods of up to 12 months. There are no recommendations so far regarding triple therapy with Xa inhibitors. We must also realize that the doses of rivaroxaban for ACS (2.5 or 5 mg twice daily)²⁴ are widely different from the doses for AF (20 mg once daily).²²

Several unexplored issues remain: first, the studies have been performed with Xa inhibitors and clopidogrel; however, new and more potent antiplatelets (prasugrel, ticagerelor) have appeared, but we lack data about the safety and security of the combination of new antiplatelets (instead of clopidogrel) and Xa in post-ACS. So far, the only study comparing prasugrel vs. clopidogrel in the setting of treatment with aspirin and oral anticoagulation showed more bleeding risk in the prasugrel group, but it was underpowered for efficacy,³⁴ but we have no data on the efficacy. Secondly, new-generation stents have a lower risk of stent thrombosis, thus requiring shorter DAPT which will reduce the risk of bleeding.

Conclusions

Following an ACS, patients remain at increased risk of recurrent ischaemic events, despite optimal DAPT and revascularization. Treatment targeted towards thrombin-mediated pathways of platelet aggregation and activation offer an attractive therapeutic target in minimizing such adverse events, as thrombin abundance characterizes the cellular milieu in the immediate period after ACS. Results to date have been mixed as some studies have demonstrated significant increases in bleeding risk without improvements in clinical outcomes when used in conjunction with DAPT. Of the currently available antithrombotics, only the direct Xa inhibitor rivaroxaban appear to hold the most promise in the management of patients with recent ACS, although the burden of missing data in the ATLAS-TIMI 51 trial requires some caution when analysing its results.

Funding

This work was supported in part by grants from Ministry of Science and Education of Spain (SAF2010-16549), and Instituto de Salud Carlos III (Tercel-RD12/0012/0026) to L.B.

Conflict of interest: none declared.

References