NICE guidance - rivaroxaban for preventing atherothrombotic events in people with coronary or peripheral artery disease

Last edited 10/2019 and last reviewed 05/2021

Rivaroxaban plus aspirin is recommended within its marketing authorisation, as an option for preventing atherothrombotic events in adults with coronary artery disease or symptomatic peripheral artery disease who are at high risk of ischaemic events.

For people with coronary artery disease, high risk of ischaemic events is defined as:

  • aged 65 or over, or
  • atherosclerosis in at least 2 vascular territories (such as coronary, cerebrovascular, or peripheral arteries), or
  • 2 or more of the following risk factors:
    • current smoking
    • diabetes
    • kidney dysfunction with an estimated glomerular filtration rate (eGFR) of less than 60 ml/min (note that rivaroxaban is contraindicated if the eGFR is less than 15 ml/min)
    • heart failure
    • previous non-lacunar ischaemic stroke.

Assess the person's risk of bleeding before considering rivaroxaban. Treatment should only be started after an informed discussion with them about the risks and benefits of rivaroxaban, weighing up the risk of atherothrombotic events against the risk of bleeding. The risks and benefits of continuing treatment with rivaroxaban should be regularly reviewed.

Notes (1):

  • the data presented to the NICE committee was related to the overall COMPASS trial population and also for 3 subpopulations that it identified as being at especially high baseline risk of ischaemic events: people with coronary artery disease and peripheral artery disease, people with coronary artery disease and heart failure, and people with coronary artery disease and poor kidney function
    • risk of ischaemic events is related to the person's medical history and the extent of atheroma. People with heart failure, diabetes, poor kidney function or diffuse atherosclerosis affecting several areas (such as the coronary and peripheral arteries) are at higher risk of events. However other factors also increase risk including diabetes, high body mass index and smoking. At technical engagement, it was queried whether the company's subgroups are clinically relevant and represent people at highest risk of atherothrombotic events who are likely to benefit most from treatment with rivaroxaban plus aspirin. The clinical experts agreed that although these subgroups are clinically identifiable and relevant, there are other groups of people who are also at high risk. These include people who have had myocardial infarction or stroke, and those with multi-vessel coronary disease and diabetes. These people could derive similar benefit from rivaroxaban plus aspirin as seen in the 3 subgroups, because there was no between-group heterogeneity in relative treatment effects reported in COMPASS
    • committee concluded that the efficacy results from the whole COMPASS population should be considered rather than the 3 subpopulations identified by the company, and it did not consider the subgroups further

  • primary outcome, incidence of cardiovascular death, myocardial infarction, or stroke, occurred in 4.1% of the rivaroxaban plus aspirin group vs. 4.9% of the rivaroxaban alone group vs. 5.4% of the aspirin alone group (p < 0.001 for rivaroxaban plus aspirin vs. aspirin alone; p = 0.12 for rivaroxaban alone vs. aspirin alone). The primary efficacy outcome was the same in all tested subgroups
    • NICE noted that (1) rivaroxaban plus aspirin showed a statistically significant relative risk reduction of 24% in major cardiovascular events compared with aspirin (HR 0.76, 95% confidence interval [CI] 0.66 to 0.86; p<0.001)
      • two of the individual components of the primary composite outcome also showed statistically significant relative risk reductions in the treatment arm: 42% for ischaemic stroke (HR 0.58, 95% CI 0.44 to 0.76; p<0.001) and 22% for cardiovascular death (HR 0.78, 95% CI 0.64 to 0.96; p=0.02)
      • concluded that rivaroxaban plus aspirin reduces the risk of cardiovascular events compared with aspirin alone, and that the greatest effect is for ischaemic stroke

  • primary safety outcome in COMPASS was major bleeding based on a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria
    • Major bleeding was defined as a composite of fatal bleeding, and/or symptomatic bleeding in a critical area or organ (such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, intramuscular with compartment syndrome, or bleeding into the surgical site requiring re-operation), and/or bleeding leading to hospitalisation (with or without an overnight stay)
    • risk of major bleeding, as defined by the modified ISTH criteria, increased by 70% in the rivaroxaban plus aspirin group compared with aspirin alone (HR 1.70, 95% CI 1.40 to 2.05; p<0.001)

  • COMPASS is a highly selected population that includes people at high risk of ischaemic events but excludes people with a known increased bleeding risk
    • benefits and risks of rivaroxaban plus aspirin are only known for the specific population of people in COMPASS; that is, people with a high risk of ischaemic events as defined by the inclusion criteria of the trial
    • decision to start treatment should only be taken after an informed discussion about the risks and benefits of rivaroxaban, weighing up the risk of ischaemic events against the bleeding risk
    • concluded that rivaroxaban should only be considered a treatment option for people at high risk of ischaemic events as defined by the inclusion criteria of COMPASS

  • clopidogrel is not a relevant comparator for the overall COMPASS population
    • clinical experts explained that clopidogrel is the preferred antiplatelet treatment for people with peripheral artery disease (based on NICE's technology appraisal guidance for the prevention of occlusive vascular events), but it is not a relevant comparator for the whole COMPASS population. This is because aspirin is the preferred treatment for secondary prevention of cardiovascular disease in people with stable coronary artery disease, and clopidogrel is only recommended when aspirin is unsuitable because of contraindication or hypersensitivity

  • indirect comparison of rivaroxaban against ticagrelor does not provide reliable estimates of relative effectiveness or risk of bleeding
    • concluded that COMPASS and PEGASUS have too many differences to allow a reliable estimate of the relative efficacy or bleeding risk of rivaroxaban plus aspirin compared with ticagrelor plus aspirin