For decades, warfarin was the primary anticoagulant used. Warfarin achieves its anticoagulant effect by inhibiting clotting factors II, VII, IX, and X. However, it is prone to numerous drug and food interactions, requiring regular blood tests to maintain the INR within the therapeutic range. This demands significant patient time, medical resources, and careful dose adjustments by healthcare providers, which can be challenging.^2,3

In contrast, NOACs target a single clotting factor, such as factor Xa or factor IIa (thrombin), offering a more predictable and stable anticoagulant effect with fewer drug and food interactions and no need for routine monitoring.³

In South Africa, three NOACs are available: Dabigatran, a direct inhibitor of factor IIa, as well as apixaban and rivaroxaban, which are direct inhibitors of factor Xa. All three NOACs are indicated for the reduction of stroke and systemic embolism (SE) in patients living with AFib.^4,5,6

Dabigatran was the first NOAC introduced (2010). In May this year, Pharma Dynamics introduced dabigatran etexilate, the first generic alternative to dabigatran. The new generic formulation is available in three strengths: 75mg, 110mg, and 150mg.^2,7

NOACs superior to warfarin

The superiority of NOACs as a class compared to warfarin has been shown in numerous studies. NOACs have significantly improved the safety profile and treatment adherence of patients living with AFib.²

A network-analysis by Chan et al (2024) showed that among the NOACs, only dabigatran had a lower risk of all-cause mortality than warfarin. Dabigatran was also associated with lower risks of major bleeding and intracranial haemorrhage (ICH).⁸

Costs associated with stroke treatment and care

Stroke treatment and management impose a significant economic burden on healthcare resources in terms of direct medical expenses and indirect costs. In the United States, expenditures on stroke treatment and care amount to ~R646bn annually and in Europe ~R1.312tn.⁹

In South Africa, the estimated total direct stroke treatment and care costs over a period of five-years were R7.3tn, with R2.6bn from inpatient care. The economic stroke burden was found to be higher in patients living with hypertension, cardiovascular diseases, and diabetes.¹⁰

What is the most cost-effective anticoagulant?

Although NOACs are more expensive than warfarin, a cost-utility analysis comparing warfarin (target INR 2-3), apixaban (5mg twice daily), dabigatran (150mg twice daily), rivaroxaban (20mg once daily), and no treatment, found that all NOACs showed positive incremental net monetary benefits compared to warfarin, indicating their cost-effectiveness.^9,11

According to a costing report compiled by the British National Institute of Health and Care Excellence, dabigatran offers a greater reduction in stroke risk, which significantly impacts expected costs and quality-adjusted life years (QALYs).¹¹

Similarly, Wu et al found that based on the incremental cost-effectiveness ratio (ICER) of ~R743 000 per QALY, NOACs are cost-effective. In many healthcare systems, treatments with an ICER below certain thresholds (eg typically ~R878 000 to ~R1.7m per QALY in the United States) are considered good value for the health benefits they provide.¹²

In the South African context, a 2013 study by Bergh et al found that dabigatran was cost-effective, with an ICER of ~R93 290 per QALY gained, compared to warfarin. Avoiding INR testing with dabigatran reduces the ICER by up to 15.7%.¹³

How effective is dabigatran etexilate and how does the cost compare to the originator?

Generic medicines are defined as those containing the same active substances, with identical strength, dosage form, and route of administration as their branded counterparts.¹⁴

They meet comparable standards for therapeutic equivalence. Unlike originator firms, generic manufacturers do not bear the research and development costs, allowing them to offer medicines at significantly lower prices - typically between 20% and 90% less.¹⁴

Generic medicines have become a crucial competitive factor in the pharmaceutical market, capturing significant market share once the patents of originator medicines expire. In South Africa, policies supporting generics, along with increased registration and improved patient acceptance, have resulted in a steady rise in the use of generic medicines.¹⁴

Dabigatran etexilate is a small molecule pro-drug with no direct pharmacological activity. Once administered orally, it is rapidly absorbed and converted to dabigatran by esterases in the plasma and liver. Dabigatran acts as a competitive, reversible direct thrombin inhibitor, the active component in plasma.¹⁵

Thrombin, a serine protease, converts fibrinogen into fibrin during coagulation, and inhibiting it prevents thrombus formation. Dabigatran also inhibits free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation.¹⁵

According to Sorenson et al, patients treated lifelong with dabigatran etexilate experienced fewer ICH (0.49 for dabigatran etexilate vs 1.13 for warfarin) and fewer ischaemic strokes (4.40 for dabigatran etexilate vs 4.66) per 100 patient-years.¹⁶

The ICER of dabigatran etexilate was ~R183 000 per QALY compared to warfarin. This study highlights the cost-effectiveness of dabigatran etexilate as an alternative for stroke and SE prevention.¹⁶

Conclusion

While warfarin has long been the standard anticoagulant for stroke prevention in AFib, dabigatran offers clear advantages in both clinical outcomes and cost-effectiveness. Dabigatran provides a significant reduction in stroke risk and ICH compared to warfarin, with fewer drug and food interactions, and eliminates the need for routine INR monitoring, thus reducing overall healthcare costs.

Although dabigatran has a higher upfront cost, its long-term cost-effectiveness is well-documented, particularly when considering the avoidance of stroke-related costs.

Furthermore, the introduction of generic dabigatran etexilate in South Africa offers even greater cost savings, as generic versions are typically 20% to 90% cheaper than the originator, making it a more affordable and accessible option for both patients and healthcare systems. This reinforces the value of dabigatran, especially in its generic form, as a cost-effective alternative to warfarin for stroke prevention in atrial fibrillation.

References

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2. Wadhera RK, Russel CE, Piazza G. Warfarin Versus Novel Oral Anticoagulants: How to Choose? Circulation, 2014.
3. Hicks T, Steward F, Eisinga A. NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. BMJ, 2015.
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8. Chan Y-H, C S-W, Chan C-Y, Chao T-F. Comparative safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in patients with non-valvular atrial fibrillation: A network meta-analysis. Journal of the Formosan Medical Association, 2024.
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11. NICE guideline No 196. Anticoagulant therapy for stroke prevention in people with atrial fibrillation: Diagnosis and management. Evidence review G1 National Guideline Centre (UK) London: National Institute for Health and Care Excellence (NICE) 2021 Apr. ISBN-13: 978-1-4731-4043-1
12. Wu Y, Zhang C, Gu Z-C, et al. Cost-Effectiveness Analysis of Direct Oral Anticoagulants Vs. Vitamin K Antagonists in the Elderly with Atrial Fibrillation: Insights from the Evidence in a Real-World Setting. Front Cardiovasc Med, 2021.
13. Bergh M, Marais CA, Miller-Jansön H, et al. Economic appraisal of dabigatran as first-line therapy for stroke prevention in atrial fibrillation. SAMJ, 2013.
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15. Professional Information. Dabiklot. 2023. [Internet]. Available at: https://www.medicalacademic.co.za/wp-content/uploads/sites/2/2024/06/A5207_Dabiklot_PIPIL_Nov23.pdf 
16. Sorensen SV, Kansal AR, Connolly S, et al. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective. Thromb Haemost. 2011.