Optimising anticoagulation: Apixaban vs rivaroxaban selection

It is estimated that ~10% of adults ≥75-years have atrial fibrillation (AFib). AFib results in uncoordinated contractions of the heart’s atria, which can lead to the formation of blood clots. These clots increase the risk of stroke five-fold and can also contribute to cognitive decline, renal impairment, and mesenteric ischaemia.1

Studies show that ~20% of strokes occur in patients with known AFib who were either inadequately anticoagulated or inappropriately treated with antiplatelet drugs.1

Stroke recovery can be complicated by venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). The risk of VTE is highest within the first three months following a stroke, decreasing rapidly afterward.2 

Although symptomatic PE occurs in only about 1% of stroke survivors within the first two- to four-weeks, it remains a significant cause of preventable death, accounting for up to 30% of post-stroke fatalities. Stroke-related VTE has also been linked to increased disability at six months and lower survival rates at 30-days and one-year post-stroke.2

It is therefore extremely important to evaluate patients’ stroke risk, and those identified as high-risk should start treatment with non-vitamin K oral anticoagulants (NOACs) as the primary antithrombotic therapy, according to Giskes et al.1

NOACs are direct-acting medications that specifically target either thrombin (factor IIa) or activated factor X (Xa). Evidence indicates that NOACs are at least as effective as, if not superior to, warfarin in reducing the risk of stroke, with similar or lower rates of bleeding compared to warfarin.1

NOACs reduce stroke risk by ~70% and mortality by ~30%. Intracranial haemorrhage (ICH) rates are significantly lower with NOACs compared to warfarin, and the incidence of major gastrointestinal (GI) bleeding is comparable between NOACs and warfarin.1

NOACs offer practical benefits in clinical settings, including fewer food and drug interactions and the absence of the need for frequent monitoring. They achieve full anti-coagulation within one to two hours of dosing due to their rapid onset.1

Are NOACs universally suitable for all patients?

In South Africa, the available NOACs include dabigatran, a direct inhibitor of factor IIa, and apixaban and rivaroxaban, which are direct inhibitors of factor Xa.1

All three NOACs are indicated for the prevention of VTE in patients undergoing hip or knee replacement surgery, the reduction of stroke and SE risk in patients living with AFib, and the treatment and prevention of recurrent DVT PE.3,4,5 

Dabigatran, apixaban, and rivaroxaban each serve these purposes, with slight variations. Apixaban additionally reduces the risk of mortality in patients living with NVAFib with one or more risk factors.3,4,5

Rivaroxaban and apixaban are currently among the most prescribed NOACs. However, their distinct pharmacokinetic and pharmacodynamic profiles can influence their safety and effectiveness differently.6

To anticoagulate or not?

Deciding to anticoagulate a patient involves assessing the need for anticoagulant therapy. The CHA2DS2-VASc score has expanded eligibility for anticoagulants to 90%-95% of patients, compared to the previous 66% with the CHADS2 score.9 

Given the low bleeding rates of NOACs, most patients living with NVAFib should receive anticoagulant therapy. Exceptions are patients with active bleeding, recurrent bleeding from anticoagulants, or a CHA2DS2-VASc score of 0. For patients who had major bleeding with warfarin, alternatives like apixaban or rivaroxaban should be considered before eliminating anticoagulation.9

Tailoring anticoagulation therapy

According to Bonde et al, clinical guidelines do not endorse a particular NOAC over others for stroke prevention in AFib. As a result, there is considerable variability in the choice of NOACs, leading to similar patients potentially receiving different NOACs depending on the treatment facility.7

Patient profiles that can aid in tailoring anticoagulation therapy include:9,10

• Apixaban is preferred due to its consistent efficacy in reducing bleeding outcomes, including intracranial bleeding. For younger patients with good kidney function and no bleeding history, apixaban offers significant protection from stroke.

• Apixaban is favoured over rivaroxaban for patients with a high bleeding risk due to its lower incidence of bleeding complications.

• Apixaban is recommended as it is associated with a lower rate of GI bleeding compared to rivaroxaban.

• Apixaban is suitable for patients with chronic kidney disease (CKD), including those with end-stage renal disease, as it does not require dose adjustment based on CKD stage.

• Rivaroxaban, with its once-daily dosing, can be beneficial for improving patient adherence compared to medications requiring multiple daily doses. However, comparisons between once-daily and twice-daily dosing regimens reveal that despite a higher percentage of prescribed doses being taken with once-daily dosing, twice-daily dosing ensures a greater degree of continuity in drug action.

What about patients who require extended therapy?

For the prevention of VTE following elective hip or knee replacement surgery, the recommended dose of apixaban is 2.5mg taken orally twice daily. The first dose should be administered 12- to 24-hours post-surgery. For hip replacement surgery, the treatment duration is recommended to be 32- to 38- days, while for knee replacement surgery, it is 10- to 14-days.4

According to Agnelli et al, the decision to extend treatment is challenging. In the Apixaban for the Extended Treatment of Venous Thromboembolism (AMPLIFY-EXT) the team set about evaluating the efficacy and safety of two doses of apixaban compared to placebo in patients with VTE who had completed six- to 12-months of initial anticoagulation therapy and were uncertain about continuing treatment.11 

Agnelli et al evaluated the efficacy and safety of two apixaban doses (2.5mg and 5mg twice daily) compared to placebo. The study medications were administered for 12 months.11

The results showed that among 2486 randomised patients (with 2482 included in the intention-to-treat analysis), the rate of symptomatic recurrent VTE or death from VTE was significantly lower in both apixaban groups compared to the placebo group.11 

Specifically, 8.8% of placebo recipients experienced these outcomes, while only 1.7% of those receiving either the 2.5mg or 5mg dose of apixaban did. The difference between apixaban and placebo was 7.2 percentage points for the 2.5mg dose and seven percentage points for the 5mg dose, with both comparisons reaching statistical significance.11

Regarding bleeding risks, major bleeding occurred in 0.5% of the placebo group, 0.2% in the 2.5mg apixaban group, and 0.1% in the 5mg apixaban group. Clinically relevant non-major bleeding rates were slightly higher in the apixaban groups compared to placebo. The rate of death from any cause was also lower in the apixaban groups compared to the placebo group.11

In conclusion, extended treatment with apixaban, whether at a treatment dose of 5mg or a prophylactic dose of 2.5mg, effectively reduced the risk of recurrent VTE without increasing the rate of major bleeding.11

For the prevention of stroke and SE in patients with NVAFib, the recommended dose is 5mg taken orally twice daily. However, for patients who meet at least two of the following criteria: Age ≥80-years, body weight of ≤60kg, or serum creatinine levels of ≥1.5mg/dl or higher – the recommended dose is 2.5mg twice daily.4

In the Apixaban Versus Aspirin in Patients with Atrial Fibrillation (AVERROES) trial, 5599 patients living with AFib and at least one additional stroke risk factor, who were unsuitable for VKA therapy, were enrolled at 522 sites across 36 countries.12 

Patients were randomised to receive apixaban (n=2808) or aspirin (n=2791). After a mean follow-up of 13-months, the trial was stopped early due to the clear benefit of apixaban, which significantly (55%) reduced the risk of stroke or SE compared to aspirin with similar major bleeding risk.12

Following the double-blind phase, an open-label extension was initiated, allowing participants to continue receiving apixaban. Of the 5599 participants, 58.5% continued apixaban treatment during the open-label extension, with a median follow-up of three years.12

During this period, the annual rates of stroke or SE, haemorrhagic stroke, and major bleeding were 1.0%, 0.3%, and 1.2%, respectively. These event rates were consistent with those observed during the initial trial phase.12 

An analysis of all patients who received apixaban from the start of AVERROES to the end of the extension showed similar results, supporting the long-term efficacy and safety of apixaban in patients living with AFib.12

In a retrospective cohort study by Ray et al, the team compared major ischaemic and haemorrhagic outcomes between apixaban and rivaroxaban in patients ≥65-years (n=581 451). Follow-up was four years.13

The primary outcome was a composite of major stroke/SE and haemorrhagic (ICH and other significant bleeding) events. Secondary outcomes included non-fatal extracranial bleeding and total mortality.13 

Results showed that the adjusted primary outcome rate for rivaroxaban was 16.1 per 1000 person-years compared to 13.4 for apixaban, indicating a higher risk associated with rivaroxaban. Rivaroxaban also had an increased risk for both major ischaemic events (8.6 vs 7.6 per 1000 person-years) and haemorrhagic events (7.5 vs 5.9). Additionally, patients on rivaroxaban experienced higher rates of non-fatal extracranial bleeding (39.7 vs 18.5) and total mortality (44.2 vs 41).13

Conclusion

In conclusion, both apixaban and rivaroxaban offer significant benefits in managing patients living with AFib. Apixaban is generally preferred in patients at higher risk of bleeding, particularly those with CKD or a history of GI bleeding. For extended treatment, apixaban effectively reduces the risk of recurrent VTE without increasing major bleeding, providing a safe and efficient option for long-term anticoagulation therapy. Tailoring patient selection based on individual risk profiles remains essential.

References

1. Giskes K, Lowres N, Hespe C, Freedman B. Stroke Risk Mitigation Prescribing and Monitoring Anticoagulation in Atrial Fibrillation. Modern Medicine, 2024.

2. Tøndel BG, Morelli VM, Hansen JB, Braekkan SK. Risk factors and predictors for venous thromboembolism in people with ischemic stroke: A systematic review. J Thromb Haemost, 2022.

3. Professional Information. Pradaxa. 2022. [Internet]. https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2022/08/pi-pradaxa-17aug2022.pdf 

4. Professional Information. Apixaban. 2024 [Internet]. Available at: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2024/04/Final_PIL_Apixaban-Accord_Applicant-1.pdf 

5. Professional Information. Xarelto. 2022 [Internet]. Available at: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2022/05/approved-xarelto-15-and-20-pi-05.2022.pdf 

6. Bonde AN, Martinussen T, Lee CJ-Y, et al. Rivaroxaban Versus Apixaban for Stroke Prevention in Atrial Fibrillation. An Instrumental Variable Analysis of a Nationwide Cohort. Circ Cardiovasc Qual Outcomes, 2020. 

7. Professional Information. Ixarola. 2022 [Internet]. Available at: https://pi-pil-repository.sahpra.org.za/wp-content/uploads/2022/05/approved-ixarola-15-20-pil-05.2022.pdf 

8. Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clinical Pharmacokinetics, 2019.

9. Schaefer JK, McBane RD, Wysokinski WE. How to choose appropriate direct oral anticoagulant for patients with nonvalvular atrial fibrillation. Ann Hematol, 2016. 

10. Vrijens B, Heidbuchel H. Non-vitaman K antagonist oral anticoagulants: considerations on once- vs. twice-daily regimens and their potential impact on medication adherence. Europace, 2015.

11. Agnelli G, Buller HR, Cohen A, et al. Apixaban for Extended Treatment of Venous Thromboembolism. NEJM, 2013.

12. Benz AP, Eikelboom JW, Yusuf S, et al. Long-Term Treatment with Apixaban in Patients with Atrial Fibrillation: Outcomes during the Open-Label Extension following AVERROES. Thromb Haemost, 2021.

13. Ray WA, Chung CP, Stein M, et al. Association of Rivaroxaban vs Apixaban with Major Ischemic or Hemorrhagic Events in Patients with Atrial Fibrillation. JAMA, 2021.