Design– double-blind trial involving placebo medication vs study medication, March 2013 to May 2016.
- Rivaroxaban (2.5mg bd) + aspirin (100mg od)
- Aspirin (100mg od) + placebo
- Rivaroxaban (5mg bd) + Aspirin (100mg od)
- cardiovascular death, stroke, MI
- Coronary heart disease, MI, ischemic stroke, acute limb ischemia, all-cause mortality. Major and minor bleeding
- 27,395 patients in toral. Multinational (Australia, Argentina, Canada, France, Germany, Hungary, Israel, Japan, Malaysia, Philippines, Poland, Romania, Russia, Slovakia, South Africa, South Korea, Sweden, Switzerland, Ukraine, UK, USA). In terms of patient numbers, largest cohort from Argentina (n= 2791), Netherlands (n=2522), Canada (n= 2444), Czech (n=1553).
- Australia contributes to 353 patients.
- Informed consent.
- Meet criteria for coronary arterial disease AND >65 (MI last 20 years, known IHD, needing PCI or CABG for multi-vessel disease).
- For inclusion under CAD risk AND <65, must also have documented 2 vascular beds (aorta, brain, GI tract, lower limbs, upper limbs, renal) or 2 additional risk factors (current smoker, DM, eGFR <60 ml/min, heart failure, non-lacunar infarct >1/12 ago)
- Peripheral vascular disease (previous angioplasty or bypass surgery, amputation for PVD, known PVD with claudication [ankle-BP-index <0.90 or >50% stenosis on formal angio or duplex], known carotid disease (>50% on duplex or angio).
*there are generally older patient or young patient with high risk for MI, ischemic stroke, PVD and embolic disease.
- high risk for bleeding, hepatic disease with coagulopathy
- Stroke <1/12 with hx or any hx of haemorrhagic or lacunar infarct
- EF <30% or NYHA class III or IV, eGFR <15 ml/min
- Any clinical need for dual antiplatelet therapy or oral anticoagulation
- Poor prognosis (eg metastatic cancer)
- Being on systemic therapy with inhibitor or inducer of CYP 3A4
- Pregnant, breastfeeding, no effective birth control and at risk of pregnancy
- Being on another study and on invesigational drug, known contraindication to any study related procedures
Analytic methods– Hochberg-based gatekeeping procedure (time to event outcomes)
- Outcome 1 (primary) -Composite of cardiovascular death, ischemic stroke, myocardial infarction.
- Outcome 2 (first secondary) -Composite of coronary heart disease death, ischemic stroke, myocardial infarction or acute limb ischemia
- Outcome 3 (second secondary) -Composite of cardiovascular death, ischemic stroke, myocardial infarction, or acute limb ischemia
- Outcome 4 (third secondary): mortality (all cause).
- Fewer primary outcome in rivaroxaban-plus-aspirin group (379 or 4.1%) vs aspirin-alone group (496 or 5.4%). Hazard ratio 0.76, 95% CI 0.66-0.86 (p<0.001, z=-4.126)
- More major bleeding events in rivaroxaban-plus-aspirin group (288 or 3.1%) vs aspirin-alone group (170, 1.9%). Hazard ratio 1.70, 95% CI 1.40-2.05, p<0.001)
- No significant difference in intracranial bleeding or fatal bleeding in groups. Major bleeding more common in rivaroxaban-alone group.
- Rivaroxaban (2.5mg bd) plus aspirin better cardiovascular outcomes and more major bleeding (but less intracranial or fatal bleeding) compared to those aspirin alone.