Low rates of stroke and major bleeding with rivaroxaban confirmed by global study

Results of the pooled analysis of the global XANTUS real-world study programme were announced recently at the European Society of Cardiology (ESC) Congress in Barcelona, Spain. The study investigated the use of the non-vitamin K antagonist oral anticoagulant (NOAC) rivaroxaban for stroke prevention in patients with non-valvular atrial fibrillation (AF) (irregular heart beat). The study showed low rates of both stroke and major bleeding, including fatal intracranial (skull) bleeds in AF patients on Xarelto® for stroke prevention. The majority (96.1%) of the pooled XANTUS population did not experience stroke/ systemic embolism, major bleeding and all-cause death. This is generally consistent with the Phase III ROCKET AF trial and reaffirms the safety and efficacy of rivaroxaban in AF management.

The global XANTUS programme is the largest prospective observational study on a single NOAC for stroke prevention in AF. This pooled analysis combined real-world data from three prospective, single-arm, multi-centre studies across multiple regions, which together followed more than 11,000 patients from 47 countries:

1. XANTUS, the largest of the studies, which followed 6,784 patients from Canada, Israel and 10 countries across Europe.
2. XANAP, the first Pan-Asian real-world study of rivaroxaban in AF stroke prevention, which followed 2,273 patients from 10 countries/territories in Asia (Hong Kong, S.A.R., China SAR, Indonesia, South Korea, Malaysia, Philippines, Singapore, Taiwan, China, Thailand, Vietnam and Pakistan).
3. XANTUS-EL which involved 2,101 patients from 17 countries in Eastern Europe, Middle East, Africa, and Latin America.

Unmet Needs in Atrial Fibrillation

AF is a heart condition characterised by irregular heartbeats which increases the risk of stroke caused by blood clots by five-fold. Strokes due to AF are also more severe, causing disability in over 50% of patients and generally worse outcomes than strokes due to other causes. The incidence of AF increases with age.

The prevalence of AF is a global issue with the number of AF patients growing rapidly and expected to have doubled by 2050. AF is especially of concern in Asia due the regions rapidly ageing populations. It is estimated that by 2050, Asia will have 72 million AF patients, and 2.9 million among them will suffer from an AF-associated stroke.

The good news is AF-related stroke can be prevented. However, there are still a significant number of AF patients in Asia not receiving optimal anticoagulant therapy for stroke prevention. Older anticoagulant therapy with Vitamin K Antagonist (VKAs) such as warfarin makes effective anticoagulation harder for patients and physicians due to its manifold food and drug interactions, regular blood monitoring requirements and risk of intracranial (skull) bleeding. These serious disadvantages cause VKAs to be under-used or under-dosed in AF stroke prevention, leaving patients unprotected.

"NOACs like rivaroxaban can potentially address this medical challenge as they are at least as effective as traditional warfarin therapy in preventing strokes in AF patients, but are easier to administer and carry a significantly lower risk of the life-threatening intracranial bleeding," said Professor John Camm, the Professor of Clinical Cardiology at St George’s University of London who presented the results at ESC. "While this has been well proven in clinical trials and real-world studies, the consistency of the combined data from the worldwide XANTUS programme adds significantly to our understanding on the safety of NOACs in AF patients, and gives physicians the confidence to prescribe rivaroxaban in daily clinical practice."

In the XANTUS pooled analysis, a total of 11,121 patients were enrolled into the three real-world studies and included in the analysis. Patients were from 47 countries in Western Europe/ Canada/Israel (47.5%), Eastern Europe (23.2%), East Asia (20.1%), the Middle East/Africa (6.2%) and Latin America (3.0%). The majority of patients (73.1%) initially received rivaroxaban 20mg once daily, while 25.1%, 1.6% and 0.2% of patients received rivaroxaban 15mg once daily, 10mg once daily and other doses, respectively. There were differences in patient demographics, clinical characteristics as well as stroke and bleeding risks among the study regions. Patients with higher CHADS2 (stroke risk) or CHA2DS2-VASc (bleeding risk) scores at baseline were more likely to experience major bleeding, stroke /systemic embolism or death¹.

Results from XANTUS pooled population showed low rates of both stroke and major bleeding with rivaroxaban at 0.9% and 1.7% per year respectively, generally consistent with those in the ROCKET AF trial. Mean CHADS2 (stroke risk) and CHA2DS2-VASc (bleeding risk) scores for the pooled population were 2.0 and 3.5 respectively.

The findings were generally consistent across different regions and patient populations worldwide based on each of the individual studies. In XANAP, the Asian arm of XANTUS programme, the rates of both stroke and major bleeding were low at 1.7% and 1.5% respectively, generally consistent with Phase III ROCKET AF East Asia study and two other studies in the programme. CHADS2 (stroke risk) and CHA2DS2-VASc (bleeding risk) scores in XANAP were 2.3 and 3.7 respectively, higher than the mean scores of the XANTUS pooled population The majority (96.6%) of patients on rivaroxaban in the study did not experience stroke / systemic embolism, major bleeding, and all-cause death⁽³⁾ .

The XANTUS Pooled Analysis is a pre-planned pooled analysis of the prospective, observational XANTUS, XANAP and XANTUS-EL studies of unselected patients with AF newly starting rivaroxaban for stroke prevention. Patients were followed for 1 year, at ∼3-month intervals, or for ≥30 days after permanent discontinuation. Primary outcomes were major bleeding, adverse events (AEs) or serious AEs (SAEs) and all-cause mortality. Secondary outcomes included symptomatic thromboembolic events and non-major bleeding. Treatment-emergent major outcomes were adjudicated by a central committee. 11,121 patients were included (Western Europe/Canada/Israel: 47.5%; Eastern Europe: 23.2%; East Asia: 20.1%; Middle East and Africa: 6.2%; and Latin America: 3%). Of the patients 73.1% received rivaroxaban 20mg once daily (od) and 25.1% rivaroxaban 15mg (od); 72.4% had prior anticoagulation therapy. Mean age was 70.5 years and mean weight was 80.0kg. Co-morbidities included congestive heart failure (21.2%), hypertension (76.2%), diabetes mellitus (22.3%), prior stroke/non-central nervous system (CNS) systemic embolism (SE)/transient ischaemic attack (TIA; 21.3%) and prior myocardial infarction (MI; 8.9%). Rates of treatment-emergent major outcomes were: major bleeding 1.7 (1.5–2.0); all-cause mortality 1.9 (1.6–2.2); stroke/non-CNS SE 1.0 (0.8–1.2); stroke 0.9 (0.7–1.1).

XANAP is the first Pan-Asian, prospective, single-arm, observational study of 2,273 patients designed by Bayer to evaluate the safety and effectiveness of rivaroxaban for stroke prevention with non-valvular AF from 435 sites across Asia (Hong Kong, S.A.R., China SAR, Indonesia, South Korea, Malaysia, Philippines, Singapore, Taiwan, China, Thailand, Vietnam and Pakistan) in routine clinical practice. All treatment and dosing decisions were at the discretion of the treating physicians and patients were followed up for one year or until 30 days after premature discontinuation. Bleeding events and major thromboembolic events were centrally adjudicated by an independent committee.

At the end of the study, the majority (96.6%) of patients on rivaroxaban did not experience stroke/ systemic embolism, treatment-emergent major bleeding, and all-cause death. Overall, patients experienced treatment-emergent major bleeding at a rate of 1.5 per 100 patient-years (1.5% per year); most of these major bleeds were treated using standard clinical measures. Rates of fatal bleeding were 0.2 per 100 patient-years 0.2% per year). Critical organ bleeding occurred at a rate of 0.8 per 100 patient-years (0.8% per year), which included intracranial bleeding at a rate of 0.7 per 100 patient-years (0.7% per year). Stroke occurred at a rate of 1.7 per 100 patient-years (1.7% per year). The analyses from this study provide valuable insights on the usage of rivaroxaban by patients in Asia for non-valvular AF stroke prevention.

"Strokes in AF patients are highly preventable. These robust findings further support rivaroxaban as a therapy of choice for stroke prevention in AF patients, with a low rate of major bleeding," said Dr Foo Chuan Kit, Head of Medical Affairs of Bayer Pharmaceuticals Division for Asia-Pacific. "By involving Asian patients in this worldwide programme, we offer valuable insights to help physicians in the region safely and effectively lower the risk of stroke in their AF patients."