Worldwide Trends in Antithrombotic Therapy Prescribing for Atrial Fibrillation

Observations on the 'Transition Era' to Non-vitamin K Antagonist Oral Anticoagulants

Leona A. Ritchie; Deirdre A. Lane; Gregory Y.H. Lip


Europace. 2022;24(6):871-873. 

The landscape of atrial fibrillation (AF) management has changed substantially over the last decade. Key milestones for stroke prevention have included the introduction of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs), replacement of the CHADS2 stroke risk assessment with CHA2DS2-VASc, guideline updates to offer oral anticoagulants (OAC) to prevent AF-related stroke instead of antiplatelet therapy, and a preference to prescribe NOAC instead of VKA (Figure 1). These changes have increased the proportion of OAC eligible AF patients and have been the catalyst for the 'transition era', where we have moved away from a period dominated by VKA use for stroke prevention, to a new era of NOACs. In addition, adherence to more holistic approach to AF management, based on the Atrial fibrillation Better Care (ABC) pathway[1] is associated with improved outcomes, including a reduction in stroke.[2]

Figure 1.

Timeline of key milestones including oral anticoagulant approvals and updates to European, Asian, and American guidelines on atrial fibrillation. ACC/AHA/HRS, American College of Cardiology/American Heart Association/Heart Rhythm Society; APHRS, Asia Pacific Heart Rhythm Society; CHADS2, stroke risk assessment scoring 1 point each for history of heart failure, hypertension, diabetes, age ≥75 years, and 2 points for history of stroke/transient ischaemic attack; CHA2DS2-VASc, stroke risk assessment scoring 1 point each for female gender, age 65–74 years, history of heart failure, diabetes, hypertension, vascular disease, and 2 points each for history of stroke/transient ischaemic attack/venous thromboembolism and age ≥75 years; EMA, European Medicines Agency; ESC, European Society of Cardiology; FDA, Food and Drug Administration; NMPA, National Medical Products Administration (formerly the China Food and Drug Administration); NOAC, non-vitamin K antagonist oral anticoagulant; PMDA, Pharmaceuticals and Medical Devices Agency; VKA, vitamin K antagonist

In the latest guidelines, NOACs are recommended as the default stroke prevention strategy for all eligible AF patients, except those at low risk of thrombo-embolic events (defined as a CHA2DS2-VASc of 0 in males or 1 in females).[3,4] Non-vitamin K antagonists continue to be the only treatment option in people with antiphospholipid syndrome, advanced chronic kidney disease (creatinine clearance <15 mL/min), rheumatic mitral valve disease, or mechanical heart valves.

In the current issue of Europace, Grymonprez et al.[5] performed a systematic review and meta-analysis of worldwide antithrombotic (VKA, NOAC, antiplatelet) prescribing patterns for AF between 2010 and 2018. The review included 21 observational cohort studies set in Europe (n = 11), North America (n = 3), Asia (n = 4), Oceania (n = 1), or South America (n = 1), and one worldwide study. The annual prevalence and incidence of OAC use were reported for 9 758 637 and 197 483 non-selected AF patients eligible for OAC, respectively.[5] The authors use the term 'non-selected AF patients' to describe the exclusion of studies that reported on selected AF subgroups, including people with chronic kidney disease, dementia, a history of stroke/bleeding, older people, or those receiving interventions such as ablation or percutaneous coronary intervention.

The main findings were that worldwide prevalence and incidence of OAC use almost doubled from 0.42 [95% confidence interval (CI) 0.22–0.65] and 0.43 (95% CI 0.37–0.49) in 2010 to 0.78 (95% CI 0.77–0.78) and 0.75 (95% CI 0.74–0.76) in 2018, respectively.[5] Globally, there was a downward trend in prevalent and incident VKA prescription from 2010 to 2018 [prevalent VKA prescription: 0.42 (95% CI 0.22–0.65) in 2010 to 0.32 (95% CI 0.32–0.32) in 2018; incident VKA prescription: 0.42 (95% CI 0.36–0.49) in 2010 to 0.06 (95% CI 0.06–0.07) in 2018].[5] Conversely, there was an upward trend in prevalent and incident NOAC prescription from zero in 2010 [NOAC introduction] to 0.45 (95% CI 0.45–0.46) and 0.68 (95% CI 0.67–0.69) in 2018, respectively.[5] As expected, the prevalence of single antiplatelet use decreased from 0.37 (95% CI 0.32–0.42) in 2010 to 0.09 (95% CI 0.09–0.10) in 2018.[5] Intercontinental prescribing patterns were reported to be largely comparable, but a staggered uptake of NOAC prescribing was observed with increases first seen in North America (2011), followed by Europe and Asia (2013).[5] Between 2010 and 2018, prevalent NOAC use was consistently lower in Asia compared to North America and Europe.[5] Arguably one of the most poignant findings was that one-quarter of OAC eligible AF patients was still not prescribed OAC, suggesting that under-prescription of OAC for AF remains a global challenge.[5]

The authors should be commended for their in-depth synthesis on worldwide antithrombotic prescribing patterns that spans a decade and covers the transition era from VKA to NOAC. Grymonprez et al.[5] contextualize their findings in relation to dates of regulatory body (i.e. Food and Drug Administration, European Medicines Agency) approval for NOAC therapy, guideline updates recommending NOAC over VKA, and intercontinental variation in direct to consumer marketing and NOAC reimbursement criteria. It is noteworthy that differences in the burden of AF between continents may also affect access to, and quality of AF stroke prevention services. North America is reported to have the highest prevalence rates of age-standardized AF (>900 per 100 000), in addition to some countries in Europe, including Great Britain and Sweden.[3,6] In contrast, Africa appears to have the lowest prevalence rate (<600 per 100 000) in addition to some countries in Asia, including China.[3,6] Caution is advised when interpreting observed geographical differences because results reported for some continents were limited to one or two country-specific studies per year.

The finding that OAC therapy is under-prescribed to eligible AF patients highlights the need for research that not only explores patient-related barriers to OAC prescription but also investigates prescriber and healthcare system barriers. A recent cross-sectional study of 592 Chinese patients with AF reported self-paying as the strongest, independent predictor of OAC non-prescription (odds ratio 1.82, 95% CI 1.14–2.93), highlighting that more attention needs to be paid on the economic management of AF care in countries that do not follow a universal healthcare model.[7] Grymonprez et al. discuss the predictors/non-predictors of OAC prescription identified within their included studies. Participant characteristics including older age, dementia, frailty, multi-morbidity, and high bleeding risk were listed as some reasons for OAC non-prescription. The latest European Society of Cardiology guidelines (2020) provide definitive prescribing guidance in these patient groups, stating that older age, frailty, and multi-morbidity are not justifiable reasons for OAC non-prescription.[3] Further, in people with recent bleeding guidelines advocate re-initiation of OAC as soon as feasible after the underlying pathophysiology has been addressed.[3] It would be interesting to evaluate the impact of this guidance uptake on prescribing patterns in these AF patient subgroups pre- and post-2020.

Grymonprez et al. only included data on non-selected AF patients to reduce confounding that may arise from different OAC prescribing practices across healthcare settings and patient groups. This limits the generalizability of study findings. It is difficult to draw meaningful conclusions about worldwide OAC prescribing patterns across 'typical' AF populations that are far from homogeneous. There is no 'one OAC fits all' approach for AF-related stroke prevention and prescribing decisions should be informed by patients' clinical characteristics and personal preferences. To date, there have been no head-to-head randomized controlled trials comparing individual NOACs, but indirect analyses have been carried out using data from real-world studies and the landmark NOAC randomized trials.[8,9] The latest CHEST guidelines make NOAC-specific recommendations for different AF subgroups, allowing us to 'fit the drug to the patient profile' (and vice versa).[10] For example, the prescription of dabigatran (150 mg twice daily, as appropriate) in people with recurrent thrombotic events (i.e. aiming for potency),[8] and use of apixaban in patients at a high risk of gastrointestinal bleeding (aiming for safety).[8,9] European guidelines do not make NOAC-specific recommendations, but do re-iterate the NOAC dose selection criteria that is dependent on patient age, renal function, weight, concomitant medications, and body weight.[3]

In summary, OAC prescribing patterns have followed the predicted trajectory in keeping with guideline updates over the last decade. Prescription of OAC therapy for AF should be individualized, taking into account patient preferences and clinical history. Future research to evaluate prescribing patterns of individual NOACs in different AF subgroups is warranted as more data emerges to guide NOAC-specific prescribing decisions. In order to address OAC under-prescription in eligible AF patients, more research is needed to determine strategies to break-down prescriber and facility barriers to OAC prescription, especially in countries that do not follow a universal healthcare system.