The combination of rivaroxaban and aspirin compared with aspirin alone significantly reduced cardiovascular outcomes in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD), a large study has shown.¹ However, when rivaroxaban therapy was discontinued at the end of the trial the benefits were lost and a higher stroke rate was seen in those originally randomised to combination therapy.²

The COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) involved 27, 395 patients with CAD or PAD. Initial findings, published in the NEJM, showed that the combination of low-dose rivaroxaban 2.5 mg twice a day and aspirin 100 mg once daily reduced the risk of the composite outcome of myocardial infarction (MI), stroke or cardiovascular death by 24% compared with aspirin alone.

Even allowing for an increase in bleeding the net benefit was still statistically significant. There was also a 47% reduction in the risk of major adverse limb events (e.g. acute limb ischaemia and amputation) and an 18% reduction in mortality.¹

The trial had been planned to last 3-4 years but was halted early after a median follow-up of 23 months showed clear evidence that the combination of low-dose rivaroxaban and aspirin was beneficial.

At the end of the trial, all participants were told to stop taking the trial medications and switch to non-study low-dose aspirin (75-100 mg) once daily while awaiting regulatory approval for the trial treatment regimen.

The authors of this recent study, published in Heart, compared the rates of MI, stroke or cardiovascular death per 100 person-years during randomised treatment (n = 18, 278) and after switching to non-study aspirin at trial cessation (n = 14, 068).²

During randomised treatment, the combination of rivaroxaban and aspirin compared with aspirin alone significantly reduced the following outcomes:

• Composite outcome (MI, stroke or cardiovascular death) 2.2 vs 2.9/100 person-years, hazard ratio (HR) 0.76 (95% CI: 0.66-0.86)

• Stroke 0.5 vs 0.8/100 person-years, HR 0.58 (95% CI: 0.44-0.76)

• Cardiovascular death 0.9 vs 1.2/100 person-years, HR 0.78 (95% CI: 0.64-0.96)

During the first 12 months after early cessation, participants originally randomised to the combination compared with those randomised to aspirin had similar rates for the following:

• Composite outcome 2.1 vs 2.0/100 person-years, HR 1.08 (95% CI: 0.84-1.39)

• Cardiovascular death 1.0 vs 0.8/100 person-years, HR 1.26 (95% CI: 0.85-1.86)

However, a higher stroke rate 0.7 vs 0.4/100 person-years, HR 1.74 (95% CI: 1.05-2.87) was seen in those originally randomised to combination therapy.

This included a significant increase in ischaemic stroke during the first six months after switching to non-study aspirin; (25 vs 7 events, 0.9 vs 0.2/100 person-years, HR 3.55 (95% CI: 1.54-8.21)

The authors conclude that in people with chronic CAD or PAD discontinuing rivaroxaban and aspirin and switching to aspirin alone was associated with a loss of the cardiovascular benefits of the combination and an excess of stroke.

This raises the wider issue of access to trial therapies post-trial particularly when these therapies have been shown to be effective during the trial.

The investigators state: ‘Our study suggests that in people with chronic CAD or PAD, discontinuation of rivaroxaban 2.5 mg two times per day and aspirin

100 mg once daily and switching to non-study aspirin was associated with a loss of benefits of the combination and an excess of stroke.

‘Our results highlight that extended interruption or discontinuation of low-dose rivaroxaban in people with chronic CAD or PAD should be avoided, even if low-dose aspirin is maintained, unless there is [a] major medical reason,’ they add.