XARELTO (rivaroxaban)

Key points

Approval of reimbursement of XARELTO 2.5 mg (rivaroxaban) for the prevention of atherothrombotic events, in combination with acetylsalicylic acid, only in adult patients with severe obliterating arteriopathy of the lower limbs (OALL) who have recently undergone a successful surgical or endovascular lower limb revascularisation procedure, for whom XARELTO 2.5 mg (rivaroxaban) is initiated within 10 days of revascularisation.

Disapproval of reimbursement in other clinical marketing authorisation situations.

herapeutic improvement?

No progress in the therapeutic strategy for the prevention of atherothrombotic events in adult patients with severe obliterating arteriopathy of the lower limbs (OALL) who have recently undergone a successful lower limb revascularisation procedure.

Role in therapeutic strategy?

The management of stable coronary artery disease and peripheral arterial disease focuses primarily on reducing symptoms and preventing future cardiovascular events, including death. This is based on the management of the patient's lifestyle and on the control of risk factors, in particular through medication.

In chronic coronary syndrome (coronary artery disease), secondary prevention drug treatment includes a combination of antithrombotic agents, lipid-lowering drugs, ACE inhibitors or angiotensin-2 receptor blockers (ARBs). Antithrombotic treatment is tailored to the individual coronary patient according to ischaemic risk, bleeding risk and the clinical context. In patients in sinus rhythm with a history of infarction or myocardial revascularisation:

• low-dose aspirin (75-100 mg per day) is recommended;
• clopidogrel is recommended as an alternative to aspirin in cases of aspirin intolerance (off-label use);
• clopidogrel may be preferred to aspirin in patients with peripheral arterial disease (symptomatic or otherwise), and in those with a history of ischaemic stroke or transient ischaemic attack.

In patients at high or moderate risk of ischaemia, the combination of a second antithrombotic agent (antiplatelet agent or direct oral anticoagulant) with aspirin for long-term secondary prevention should be considered in patients at high risk of ischaemic events and in the absence of a high risk of bleeding.

In symptomatic peripheral arterial disease (PAD) for the secondary prevention of atherothrombotic events, an antiplatelet agent is indicated in patients with symptomatic PAD or who have undergone a revascularisation procedure. In obliterative arterial disease of the lower limbs (OALL) – the most common PAD – various national and international guidelines recommend long-term antiplatelet therapy with aspirin (75 to 325 mg/day) or clopidogrel (75 mg/day) in symptomatic patients (grade IA). This treatment is also recommended for patients who have undergone revascularisation. After percutaneous peripheral revascularisation with stenting, dual therapy with low-dose aspirin and clopidogrel is recommended for 1 month. Thereafter, because of the arterial disease and the high cardiovascular risk, anti-platelet therapy (aspirin or clopidogrel) is continued on a long-term basis.

In patients with a stent for non-atheromatous causes, no recommendations have been established.

In the case of asymptomatic OALL, there is no indication for prescribing an antiplatelet agent as a first-line treatment.

Role of the medicinal product

As a reminder, based on the results of the COMPASS study, the Committee deemed that XARELTO 2.5 mg (rivaroxaban) had no place in the therapeutic strategy for the secondary prevention of atherothrombotic events in patients with coronary artery disease and/or peripheral arterial disease at high risk of ischaemic events (see Committee opinion of 9 October 2019).

Based on the results of the new VOYAGER-PAD study evaluating XARELTO 2.5 mg (rivaroxaban) in combination with acetylsalicylic acid versus acetylsalicylic acid alone, with or without clopidogrel, in adult patients with severe OALL who have recently undergone a successful lower extremity revascularisation procedure, including:

• the modest benefit of adding XARELTO 2.5 mg (rivaroxaban) to antiplatelet therapy in terms of reduction of ischaemic events, mainly due to areduction of acute lower limb ischaemia, with no gain in mortality over a median follow-up time of 28 months;
• uncertainty about a possible excess risk of cardiovascular death with rivaroxaban 2.5 mg in patients who have undergone endovascular revascularisation, not suggested by the data for patients who have undergone surgical revascularisation;
• the associated increased risk of major and non-major bleeding events, but without an increased risk of fatal or intracranial bleeding;

The Committee deems that the prescription of XARELTO 2.5 mg (rivaroxaban), for the secondary prevention of atherothrombotic events , may be considered only for adult patients with severe OALL who have recently undergone successful surgical or endovascular lower limb revascularisation, and only if the clinician judges the risk/benefit balance of this treatment to be favourable.

If dual antiplatelet therapy combining clopidogrel and acetylsalicylic acid is warranted, it should be short term (53.0% of patients in the VOYAGER-PAD study received basic treatment with clopidogrel for a median of 31 days).

No studies have yet been conducted to assess the benefit of the rivaroxaban 2.5 mg/acetylsalicylic acid combination compared to clopidogrel alone, another antiplatelet agent recommended for long-term use after revascularisation in patients with severe OALL.

XARELTO 2.5 mg (rivaroxaban) should not be used in patients who have recently undergone revascularisation procedures and are already receiving dual antiplatelet therapy due to a history of stroke or TIA, as they were not evaluated in the VOYAGER-PAD study.

The Committee wishes to emphasise the importance of regular reassessment of prolonged anticoagulant therapy to take into account any new clinical evidence that may call into question the appropriateness of its continuation. The duration of treatment will be determined on a case-by-case basis for each patient, taking into account the risk of thrombotic events versus the risk of bleeding. It should be noted that to date, there is no data documenting the value of maintaining rivaroxaban 2.5 mg beyond three years of treatment (median follow-up time of 28 months in VOYAGER-PAD).

XARELTO 2.5 mg (rivaroxaban) has no place in the prevention of atherothrombotic events in adult patients with symptomatic coronary artery disease at high risk of ischaemic events.