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Low-dose anticoagulation with rivaroxaban added to standard therapy for the secondary prevention of atherothrombotic events in patients with a recent acute coronary syndrome

On The Horizon Rapid Review NPC Logo

21st March 2012

The ATLAS ACS 2-TIMI 51 trial (n = 15,526) found that rivaroxaban at twice daily doses of 2.5 mg or 5 mg, in addition to standard care, reduced the risk of the composite of cardiovascular (CV) death, myocardial infarction (MI) or stroke in patients with a recent acute coronary syndrome (ACS) compared to standard care plus placebo. Patients who took rivaroxaban were at increased risk of TIMI major bleeding not related to coronary artery bypass grafting (CABG).

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.

Action
Prescribers should follow NICE guidance for the secondary prevention of ACS. CG94 covers the early management of unstable angina and non-ST-segment-elevation myocardial infarction (NSTEMI) and CG48 covers secondary prevention in primary and secondary care for patients following an MI. Readers should also be familiar with the NICE guidance for i) the use of prasugrel in combination with aspirin for preventing atherothrombotic events in people with ACS having percutaneous coronary intervention (PCI) and ii) the use of ticagrelor plus low-dose aspirin as a treatment option in adults with ACS who meet certain criteria.

Rivaroxaban is not currently licensed for the secondary prevention of atherothrombotic events in patients with a recent ACS, but should it obtain a licence, commissioners should consider with stakeholders those patients for whom it might be appropriate. They may wish to bear in mind that patients in this trial were relatively young, with fewer co-morbidities such as renal disease, compared to patient data available from a national clinical registry database. When assessing patients with ACS for treatment with an anticoagulant, clinicians need to take into account the patient’s baseline risk of bleeding and the likely benefit from treatment.

This study represents the best available evidence relating to rivaroxaban for this indication. These data, together with their limitations, should be taken into account by local decision-makers when planning for this proposed licence extension and the commissioning of appropriate services. Local decision-makers may need to consider additional published data about this product as they emerge.

What is the background to this?
The NICE Clinical Guideline, CG94 on unstable angina and NSTEMI recommends clopidogrel in addition to aspirin for patients with ACS and a predicted 6-month mortality of more than 1.5% and no contraindications (for example, an excessive bleeding risk). Treatment with clopidogrel in combination with low-dose aspirin should be continued for 12 months after the most recent acute episode of non-ST-segment-elevation ACS. Thereafter, standard care, including treatment with low-dose aspirin alone, is recommended. Guidance on the use of a combination of aspirin and clopidogrel after an ST-segment-elevation MI can be found in NICE Clinical Guideline, CG48.

NICE guidance on prasugrel states that prasugrel in combination with aspirin is an option for preventing atherothrombotic events in people with ACS having PCI only when certain criteria are met. Ticagrelor plus low-dose aspirin is recommended by NICE for up to 12 months as a treatment option in adults with ACS who meet defined criteria.

The activation of coagulation mechanisms plays a central role in the pathogenesis of ACS. It is known that patients remain at risk of recurrent CV events after an ACS. The use of an anticoagulant, in addition to antiplatelet therapy, for secondary prevention has been explored in the past two decades with limited success. For example, the use of long-term warfarin has been limited by adverse events and the difficulties associated with drug administration.

Rivaroxaban is an oral anticoagulant that directly inhibits factor Xa and is currently marketed in 10 mg, 15 mg and 20 mg strengths for various indications. However, it is not licensed for the secondary prevention of atherothrombotic events in patients with a recent ACS. The ATLAS ACS 2-TIMI 51 trial was designed with the aim of determining a clinically effective low-dose regimen of rivaroxaban as an adjunctive therapy in patients with recent ACS. If the drug should receive licence approval for secondary prevention of atherothrombotic events in ACS, then a NICE Technology Appraisal is proposed. Currently no timeline is set for this.

Further information on the management of ACS can be found on NHS Evidence and the antiplatelet agents section of the NPC website.

What does this study claim?
The event rate estimated over two years for the primary efficacy outcome, a composite of death from CV causes, MI or stroke in the modified intention-to-treat population, was reduced in patients receiving rivaroxaban 2.5 mg or 5 mg twice daily as compared with placebo with respective rates of 8.9% and 10.7%, hazard ratio (HR) 0.84 (95% confidence interval [CI] 0.74 to 0.96), p=0.008. Therefore the number needed to treat (NNT) with rivaroxaban would be 56 over two years.

The twice daily 2.5 mg dose of rivaroxaban reduced the rates of CV deaths (2.7% versus 4.1%, HR 0.66 [95% CI 0.51 to 0.86], p=0.002) and deaths from any cause (2.9% versus 4.5%, HR 0.68 [95% CI 0.53 to 0.87], p=0.002), a survival benefit that was not seen with the twice daily 5 mg dose.

Rivaroxaban significantly increased the rate of TIMI major bleeding that was not related to CABG compared to placebo, 2.1% versus 0.6% for placebo, HR 3.96 (95% CI 2.46 to 6.38), p<0.001. Therefore number needed to harm (NNH) would be 67 over two years.

The risk of intracranial haemorrhage was also increased in patients taking rivaroxaban (0.6% versus 0.2%, HR 3.28 [95% CI 1.28 to 8.42], p=0.009), but the risk of fatal bleeding was similar between rivaroxaban and placebo at 0.3% and 0.2% respectively, HR 1.19 (95% CI 0.54 to 2.59), p=0.66.

How does this relate to other studies?
Apixaban is also a direct inhibitor of factor Xa. In the APPRAISE-2 trial, apixaban 5 mg twice daily was compared to placebo, plus standard antiplatelet therapy, in patients with a recent ACS and at least two additional risk factors for recurrent ischaemic events. The trial was stopped early because of an increase in major bleeding events with apixaban in the absence of a reduction in recurrent ischaemic events. The primary outcome of CV death, MI or ischaemic stroke occurred in 7.5% of patients who took apixaban and 7.9% in the placebo group: HR 0.95 (95% CI 0.80 to 1.11), p=0.510. Major TIMI bleeding occurred in 1.3% of patients who took at least one dose of apixaban and in 0.5% of patients on placebo, HR 2.59 (95% CI 1.50 to 4.46), p=0.001. Development of apixaban for patients with a recent ACS has now been discontinued.

Dabigatran etexilate is a direct inhibitor of thrombin. Although a phase II trial of this agent in patients with ACS has been undertaken, phase III trial development for this condition appears to have stopped.

So what?
Treatment with rivaroxaban reduced the risk of death from CV causes, MI or stroke, but this was accompanied by increased rates of bleeding. However, there was no significant increase in the rate of fatal bleeding, and the twice daily 2.5 mg dose of rivaroxaban reduced overall and cardiovascular mortality. The addition of low-dose anticoagulation with rivaroxaban may be an important development for patients with ACS, but may not be applicable to all patients seen in clinical practice. The trial had limitations in that it included few patients who were 75 years of age or over and few patients with impaired renal function. Further work is required to ascertain the drug’s role in older people with multiple co-morbidities.

The overall utility of any novel anticoagulant will depend on many factors, including efficacy, cost, risk-benefit profile, reversibility, patient convenience and satisfaction. Patients taking rivaroxaban do not need regular anticoagulant monitoring, which may influence a number of these factors (such as patient convenience), but should be balanced against others (such as reversibility).

Rivaroxaban is not currently available in 2.5 mg or 5 mg tablets, so the cost of treatment, if a licence extension is granted, is not yet known.

Study details: Mega JL, Braunwald E, Wiviott SD et al for the ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 2012;366:9-19

Design: Randomised, double-blind, placebo-controlled, event-driven, phase III trial.

Patients: 15,526 patients with symptoms suggestive of a recent ACS and a diagnosis of STEMI, NSTEMI or UA. Patients who were 18 to 54 years of age also had to have diabetes mellitus or a prior MI in addition to the index ACS event. Patients were enrolled within seven days after hospital admission for ACS, following stabilisation and initial management (such as revascularisation) of their condition.

Included patients had a mean age of 61.7 years, 37% were ≥ 65 years of age and 9.0% were ≥ 75 years of age. Half of them had experienced a STEMI as their index event. The median time between index event and randomisation was 4.7 days (range 3.2 to 6.0). Patients in each trial arm were taking similar background therapies at baseline (99% on aspirin and 93% on thienopyridines e.g. clopidogrel). In both the rivaroxaban and placebo arms of the study 93% of patients had a creatinine clearance ≥ 50ml/minute.

Patients were excluded if they had a creatinine clearance of less than 30ml/minute at screening, clinically significant gastrointestinal bleeding within the 12 months before randomisation, had a history of intracranial haemorrhage, or low haemoglobin or platelet count. Patients who had had a previous ischaemic stroke or TIA were eligible for inclusion in the study only if they were intended to be treated with aspirin only. A patient was to be excluded if they had had an ischaemic stroke or TIA and in the opinion of the treating physician needed to receive aspirin plus thienopyridine.

Intervention and comparison: Rivaroxaban 2.5 mg or 5 mg twice daily or placebo was added to standard care, including low-dose aspirin plus a thienopyridine (according to national or local guidelines). The mean duration of treatment with a study drug was 13.1 months. Maximum follow-up was 31 months.

Outcomes and results: A committee, which was blinded to treatment allocation, adjudicated all outcomes. The primary efficacy outcome was a composite of death from CV causes, MI or stroke in the modified intention-to-treat population (randomised patients and the end point events that occurred after randomisation and either no later than the completion of the treatment phase of the study, 30 days after early permanent discontinuation of a study drug, or 30 days after randomisation, for patients who did not receive a study drug). The event rates were reported as Kaplan-Meier estimates through 24 months.

Rivaroxaban reduced the primary efficacy endpoint as compared with placebo with rates of 8.9% and 10.7%, respectively, HR 0.84 (95% CI 0.74 to 0.96), p=0.008. In an analysis of the two doses of rivaroxaban, each of the doses reduced the primary endpoint as compared with placebo. The rates for patients receiving the 2.5 mg dose were 9.1% versus 10.7%, respectively (HR 0.84 [95% CI 0.72 to 0.97], p=0.02); and for the 5 mg dose 8.8% versus 10.7%, HR 0.85 (95% CI 0.73 to 0.98), p=0.03.

The 2.5 mg dose decreased the risk of CV death compared to placebo (2.7% versus 4.1%, HR 0.66 [95% CI 0.51 to 0.86], p=0.002) and death from any cause compared to placebo (2.9% versus 4.5%, HR 0.68 [95% CI 0.53 to 0.87], p=0.002). The 5 mg dose of rivaroxaban, as compared with placebo, did not significantly reduce the risk of death from either cardiovascular causes (4.0% versus 4.1%, HR 0.94 [95% CI 0.75 to 1.20], p=0.63) or any cause (4.4% versus 4.5%, HR 0.95 [95% CI 0.76 to 1.19], p=0.66).

The primary safety outcome was TIMI major bleeding not related to CABG, in all patients who received at least one dose of study drug, measured from the first dose to until two days after the end of treatment with a study drug. The risk of such bleeding increased with rivaroxaban compared to placebo with rates of 2.1% and 0.6%, respectively, HR 3.96 (95% CI 2.46 to 6.38), p < 0.001.

Rivaroxaban was associated with an increased risk of intracranial bleeding compared to placebo (0.6% versus 0.2%, HR 3.28 [95% CI 1.28 to 8.42], p=0.009). The risk of fatal bleeding was similar in both groups: 0.3% for patients given rivaroxaban versus 0.2% for placebo (HR 1.19 [95% CI 0.54 to 2.59], p=0.66. The risk with the 2.5 mg strength was less than with the 5 mg strength: 0.1% versus 0.4%, p=0.04).

Adverse events not related to bleeding were similar in the rivaroxaban and placebo groups.

Sponsorship
This study was sponsored by Johnson & Johnson and Bayer Healthcare.

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