XARELTO 2.5 mg Film-coated tablet Ref.[7073] Active ingredients: Rivaroxaban

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors
ATC code: B01AF01

Mechanism of action

Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.

Pharmacodynamic effects

Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR is only calibrated and validated for coumarins and cannot be used for any other anticoagulant.

In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC (Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC (see section 4.9).

The activated partial thomboplastin time (aPTT) and HepTest are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated, rivaroxaban levels can be measured by calibrated quantitative anti-factor-Xa tests (see section 5.2).

Clinical efficacy and safety

ACS

The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the prevention of cardiovascular (CV) death, myocardial infarction (MI) or stroke in subjects with a recent ACS (ST-elevation myocardial infarction [STEMI], non- ST-elevation myocardial infarction [NSTEMI] or unstable angina [UA]). In the pivotal double-blind ATLAS ACS 2 TIMI 51 study, 15,526 patients were randomly assigned in a 1:1:1 fashion to one of three treatment groups: rivaroxaban 2.5 mg orally twice daily, 5 mg orally twice daily or to placebo twice daily co-administered with ASA alone or with ASA plus a thienopyridine (clopidogrel or ticlopidine). Patients with an ACS under the age of 55 had to have either diabetes mellitus or a previous MI. The median time on treatment was 13 months and overall treatment duration was up to almost 3 years. 93.2% of patients received ASA concomitantly plus thienopyridine treatment and 6.8% ASA only. Among patients receiving dual anti-platelets therapy 98.8% received clopidogrel, 0.9% received ticlopidine and 0.3% received prasugrel. Patients received the first dose of rivaroxaban at a minimum of 24 hours and up to 7 days (mean 4.7 days) after admission to the hospital, but as soon as possible after stabilisation of the ACS event, including revascularisation procedures and when parenteral anticoagulation therapy would normally be discontinued.

Both the 2.5 mg twice daily and the 5 mg twice daily regimens of rivaroxaban were effective in further reducing the incidence of CV events on a background of standard antiplatelet care. The 2.5 mg twice daily regimen reduced mortality, and there is evidence that the lower dose had lower bleeding risks, therefore rivaroxaban 2.5 mg twice daily co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine is recommended for the prevention of atherothrombotic events in adult patients after an ACS with elevated cardiac biomarkers.

Relative to placebo, rivaroxaban significantly reduced the primary composite endpoint of CV death, MI or stroke. The benefit was driven by a reduction in CV death and MI and appeared early with a constant treatment effect over the entire treatment period (see Table 4 and Figure 1). Also the first secondary endpoint (all-cause death, MI or stroke) was reduced significantly. An additional retrospective analysis showed a nominally significant reduction in the incidence rates of stent thrombosis compared with placebo (see Table 4). The incidence rates for the principal safety outcome (non-coronary artery bypass graft (CABG) TIMI major bleeding events) were higher in patients treated with rivaroxaban than in patients who received placebo (see Table 6). However the incidence rates were balanced between rivaroxaban and placebo for the components of fatal bleeding events, hypotension requiring treatment with intravenous inotropic agents and surgical intervention for ongoing bleeding.

In Table 5 the efficacy results of patients undergoing percutaneous coronary intervention (PCI) are presented. The safety results in this subgroup of patients undergoing PCI were comparable to the overall safety results.

Patients with elevated biomarkers (troponin or CK-MB) and without a prior stroke/TIA constituted 80% of the study population. The results of this patient population were also consistent with the overall efficacy and safety results.

Table 4. Efficacy results from phase III ATLAS ACS 2 TIMI 51:

^a modified intent to treat analysis set (intent to treat total analysis set for stent thrombosis)
^b vs. placebo; Log-Rank p-value
^* statistically superior
^** nominally significant

Table 5. Efficacy results from phase III ATLAS ACS 2 TIMI 51 in patients undergoing PCI:

^a modified intent to treat analysis set (intent to treat total analysis set for stent thrombosis)
^b vs. placebo; Log-Rank p-value
^** nominally significant

Table 6. Safety results from phase III ATLAS ACS 2 TIMI 51:

^a safety population, on treatment
^b vs. placebo; Log-Rank p-value
^* statistically significant

Figure 1. Time to first occurrence of primary efficacy endpoint (CV death, MI or stroke):

CAD/PAD

The phase III COMPASS study (27,395 patients, 78.0% male, 22.0% female) demonstrated the efficacy and safety of rivaroxaban for the prevention of a composite of CV death, MI, stroke in patients with CAD or symptomatic PAD at high risk of ischaemic events. Patients were followed for a median of 23 months and maximum of 3.9 years.

Subjects without a continuous need for treatment with a proton pump inhibitor were randomised to pantoprazole or placebo. All patients were then randomised 1:1:1 to rivaroxaban 2.5 mg twice daily/ASA 100 mg once daily, to rivaroxaban 5 mg twice daily, or ASA 100 mg once daily alone, and their matching placebos.

CAD patients had multivessel CAD and/or prior MI. For patients <65 years of age atherosclerosis involving at least two vascular beds or at least two additional cardiovascular risk factors were required.

PAD patients had previous interventions such as bypass surgery or percutaneous transluminal angioplasty or limb or foot amputation for arterial vascular disease or intermittent claudication with ankle/arm blood pressure ratio <0.90 and/or significant peripheral artery stenosis or previous carotid revascularization or asymptomatic carotid artery stenosis ≥50%.

Exclusion criteria included the need for dual antiplatelet or other non-ASA antiplatelet or oral anticoagulant therapy and patients with high bleeding risk, or heart failure with ejection fraction <30% or New York Heart Association class III or IV, or any ischaemic, non-lacunar stroke within 1 month or any history of haemorrhagic or lacunar stroke.

Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily was superior to ASA 100 mg, in the reduction of the primary composite outcome of CV death, MI, stroke (see Table 7 and Figure 2).

There was a significant increase of the primary safety outcome (modified ISTH major bleeding events) in patients treated with rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily compared to patients who received ASA 100 mg (see Table 8).

For the primary efficacy outcome, the observed benefit of rivaroxaban 2.5 mg twice daily plus ASA 100 mg once daily compared with ASA 100 mg once daily was HR=0.89 (95% CI 0.7-1.1) in patients ≥75 years (incidence: 6.3% vs 7.0%) and HR=0.70 (95% CI 0.6-0.8) in patients <75 years (3.6% vs 5.0%). For modified ISTH major bleeding, the observed risk increase was HR=2.12 (95% CI 1.5-3.0) in patients ≥75 years (5.2% vs 2.5%) and HR=1.53 (95% CI 1.2-1.9) in patients <75 years (2.6% vs 1.7%).

The use of pantoprazole 40 mg once daily in addition to antithrombotic study medication in patients with no clinical need for a proton pump inhibitor showed no benefit in the prevention of upper gastrointestinal events (i.e. composite of upper gastrointestinal bleeding, upper gastrointestinal ulceration, or upper gastrointestinal obstruction or perforation); the incidence rate of upper gastrointestinal events was 0.39/100 patient-years in the pantoprazole 40 mg once daily group and 0.44/100 patient-years in the placebo once daily group.

Table 7. Efficacy results from phase III COMPASS:

^a intention to treat analysis set, primary analyses
^b vs. ASA 100 mg; Log-Rank p-value
^* The reduction in the primary efficacy outcome was statistically superior.
bid: twice daily; CI: confidence interval; KM %: Kaplan-Meier estimates of cumulative incidence risk calculated at 900 days; CV: cardiovascular; MI: myocardial infarction; od: once daily

Table 8. Safety results from phase III COMPASS:

^a intention-to-treat analysis set, primary analyses
^b vs. ASA 100 mg; Log-Rank p-value
bid: twice daily; CI: confidence interval; Cum. Risk: Cumulative incidence risk (Kaplan-Meier estimates) at 30 months; ISTH: International Society on Thrombosis and Haemostasis; od: once daily

Figure 2. Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction, cardiovascular death) in COMPASS:

bid: twice daily; od: once daily; CI: confidence interval

Patients after recent revascularisation procedure of the lower limb due to symptomatic PAD

In the pivotal phase III double-blind VOYAGER PAD trial, 6,564 patients after recent successful revascularisation procedure of the lower limb (surgical or endovascular including hybrid procedures) due to symptomatic PAD were randomly assigned to one of two antithrombotic treatment groups: rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily, or to ASA 100 mg once daily, in a 1:1 fashion. Patients were allowed to additionally receive standard dose of clopidogrel once daily for up to 6 months. The objective of the study was to demonstrate the efficacy and safety of rivaroxaban plus ASA for the prevention of myocardial infarction, ischaemic stroke, CV death, acute limb ischaemia, or major amputation of a vascular etiology in patients after recent successful lower limb revascularisation procedures due to symptomatic PAD. Patients aged ≥50 years with documented moderate to severe symptomatic lower extremity atherosclerotic PAD evidenced by all of the following: clinically (i.e. functional limitations), anatomically (i.e. imaging evidence of PAD distal to external iliac artery) and haemodynamically (ankle-brachial-index [ABI] ≤0.80 or toe-brachial-index [TBI] ≤0.60 for patients without a prior history of limb revascularisation or ABI ≤0.85 or TBI ≤0.65 for patients with a prior history of limb revascularisation) were included. Patients in need of dual antiplatelet therapy for >6 months, or any additional antiplatelet therapy other than ASA and clopidogrel, or oral anticoagulant therapy, as well as patients with a history of intracranial haemorrhage, stroke, or TIA, or patients with eGFR <15 mL/min were excluded.

The mean duration of follow-up was 24 months and the maximum follow-up was 4.1 years. The mean age of the enrolled patients was 67 years and 17% of the patient population were >75 years. The median time from index revascularisation procedure to start of study treatment was 5 days in the overall population (6 days after surgical and 4 days after endovascular revascularisation including hybrid procedures). Overall, 53.0% of patients received short term background clopidogrel therapy with a median duration of 31 days. According to study protocol study treatment could be commenced as soon as possible but no later than 10 days after a successful qualifying revascularisation procedure and once hemostasis had been assured.

Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily was superior in the reduction of the primary composite outcome of myocardial infarction, ischaemic stroke, CV death, acute limb ischaemia and major amputation of vascular etiology compared to ASA alone (see Table 9). The primary safety outcome of TIMI major bleeding events was increased in patients treated with rivaroxaban and ASA, with no increase in fatal or intracranial bleeding (see Table 10). The secondary efficacy outcomes were tested in a prespecified, hierarchical order (see Table 9).

Table 9. Efficacy results from phase III VOYAGER PAD:

^a intention to treat analysis set, primary analyses; ICAC adjudicated
^b composite of MI, ischaemic stroke, CV death (CV death and unknown cause of death), ALI, and major amputation of vascular etiology
^c only the first occurrence of the outcome event under analysis within the data scope from a subject is considered
^d HR (95% CI) is based on the Cox proportional hazards model stratified by type of procedure and clopidogrel use with treatment as the only covariate.
^e One sided p-value is based on the log-rank test stratified by type of procedure and clopidogrel use with treatment as factor.
^f acute limb ischaemia is defined as sudden significant worsening of limb perfusion, either with new pulse deficit or requiring therapeutic intervention (i.e. thrombolysis or thrombectomy, or urgent revascularisation), and leading to hospitalisation
^* The reduction in the efficacy outcome was statistically superior.
ALI: acute limb ischaemia; bid: twice daily; od: once daily; CI: confidence interval; MI: myocardial infarction; CV: cardiovascular; ICAC: Independent Clinical Adjudication Committee

Table 10. Safety results from phase III VOYAGER PAD:

^a Safety analysis set (all randomised subjects with at least one dose of study drug), ICAC: Independent Clinical Adjudication Committee
^b n = number of subjects with events, N = number of subjects at risk, % = 100 * n/N, n/100p-yrs = ratio of number of subjects with incident events / cumulative at-risk time
^c HR (95% CI) is based on the Cox proportional hazards model stratified by type of procedure and clopidogrel use with treatment as the only covariate
^d Two sided p-value is based on the log rank-test stratified by type of procedure and clopidogrel use with treatment as a factor

CAD with heart failure

The COMMANDER HF study included 5,022 patients with heart failure and significant coronary artery disease (CAD) following a hospitalisation of decompensated heart failure (HF) which were randomly assigned into one of the two treatment groups: rivaroxaban 2.5 mg twice daily (N=2,507) or matching placebo (N=2,515), respectively. The overall median study treatment duration was 504 days. Patients must have had symptomatic HF for at least 3 months and left ventricular ejection fraction (LVEF) of ≤40% within one year of enrollment. At baseline, the median ejection fraction was 34% (IQR: 28%-38%) and 53% of subjects were NYHA Class III or IV.

The primary efficacy analysis (i.e. composite of all-cause mortality, MI, or stroke) showed no statistically significant difference between the rivaroxaban 2.5 mg twice daily group and the placebo group with a HR=0.94 (95% CI 0.84 – 1.05), p=0.270. For all-cause mortality, there was no difference between rivaroxaban and placebo in the number of events (event rate per 100 patient-years; 11.41 vs 11.63, HR: 0.98; 95% CI: 0.87 to 1.10; p=0.743). The event rates for MI per 100 patient-years (rivaroxaban vs placebo) were 2.08 vs 2.52 (HR 0.83; 95% CI: 0.63 to 1.08; p=0.165) and for stroke the event rates per 100 patient-years were 1.08 vs 1.62 (HR: 0.66; 95% CI: 0.47 to 0.95; p=0.023). The principal safety outcome (i.e. composite of fatal bleeding or bleeding into a critical space with a potential for permanent disability), occurred in 18 (0.7%) patients in the rivaroxaban 2.5 mg twice daily treatment group and in 23 (0.9%) patients in the placebo group, respectively (HR=0.80; 95% CI 0.43 – 1.49; p=0.484). There was a statistically significant increase in ISTH major bleeding in the rivaroxaban group compared with placebo (event rate per 100 patient-years: 2.04 vs 1.21, HR 1.68; 95% CI: 1.18 to 2.39; p=0.003).

In patients with mild and moderate heart failure the treatment effects for the COMPASS study subgroup were similar to those of the entire study population (see section CAD/PAD).

Patients with high risk triple positive antiphospholipid syndrome

In an investigator sponsored, randomised open-label multicentre study with blinded endpoint adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine clearance (CrCl) <50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) of the rivaroxaban group and 2 patients (3%) of the warfarin group.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see section 4.2 for information on paediatric use).