​​​​​Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. According to data published in 2004, the prevalence of AF among Chinese residents aged 30 to 85 is 0.77%, with a prevalence of over 30% in the population aged 80 and above. Thromboembolic complications are the main cause of death and disability in AF, with stroke being the most common presentation. In non-valvular AF patients, the annual incidence of ischemic stroke (about 5%) is 2 to 7 times higher than that in non-AF patients. Preventing new and recurrent strokes should be a major component of comprehensive management strategies for AF patients. Increasing evidence shows that the rational use of anticoagulants can significantly reduce the incidence of ischemic stroke in patients at increased risk of stroke. However, most AF patients in China do not receive anticoagulant therapy. It is of great significance to further enhance the understanding of the hazards of AF and its complications, and to strengthen the prevention of thromboembolic complications (especially stroke) in order to improve patient prognosis and reduce the associated social, economic, and family burden. Currently, various oral anticoagulants are used clinically, such as warfarin and novel oral anticoagulants (dabigatran, rivaroxaban, apixaban, etc.).

Warfarin

The use of warfarin in anticoagulant therapy for AF patients: For more than 60 years, warfarin has been widely used clinically and has played an important role in the prevention of ischemic stroke in AF patients. The drug exerts its anticoagulant effect by reducing the synthesis of coagulation factors II, VII, IX, and X. Its maximum efficacy in anticoagulation is achieved after continuous medication for 4 to 5 days, and its anticoagulant effect completely disappears after discontinuation for 5 to 7 days. Several randomized clinical studies have demonstrated the role of warfarin in primary and secondary prevention of stroke in AF patients. The results show that long-term use of warfarin treatment for medium- and high-risk AF patients can effectively reduce the risk of ischemic stroke, and its efficacy is significantly better than placebo, aspirin, and aspirin combined with clopidogrel, with a relative risk reduction of 64% and an absolute risk reduction of 2.7% in the incidence of stroke per year. When only ischemic stroke is considered, dose-adjusted warfarin therapy can reduce the relative risk by 67%, and the benefit is the same for preventing the initial and recurrent strokes. Although the anticoagulant effect of warfarin is certain, the drug also has some limitations. Firstly, there is a significant variability in the degree of impact on the coagulation mechanism after warfarin is used in different individuals and cannot be predicted, resulting in a large variation in the effective dose. Secondly, the anticoagulant effect of the drug is easily affected by various foods and drugs, requiring frequent monitoring of coagulation function and timely adjustment of drug dosage during medication, which affects the long-term treatment compliance of patients. Establishing a sound AF clinic or anticoagulant treatment clinic, and systematically managing AF patients receiving anticoagulant therapy by experienced specialists, can help to overcome these limitations to some extent.

Aspirin

The role of aspirin in preventing thromboembolic events in AF patients: The value of aspirin in preventing thromboembolic events in AF patients has been controversial. Although some scholars believe that aspirin therapy may be considered for patients at low thrombotic risk (CHADS2 score 0-1), this suggestion lacks sufficient evidence. A recent large cohort study including 132,372 patients with non-valvular AF suggested that aspirin alone or in combination with warfarin does not have a significant antithrombotic effect but increases the risk of bleeding. Therefore, the role of aspirin in preventing thromboembolic events in AF patients remains to be further explored.

Dabigatran

The direct thrombin inhibitor dabigatran exerts anticoagulant effects by inhibiting thrombin (factor II). Dabigatran is a prodrug, and its active form is dabigatran. The RE-LY study provided clinical evidence for dabigatran in the long-term anticoagulant treatment of AF patients. The study aimed to evaluate the efficacy and safety of two doses of dabigatran in AF patients and compare them with warfarin. A total of 18,113 patients were included in the study, all of whom had AF confirmed by electrocardiography within 6 months before the study, with a mean CHADS2 score of 2.1. The patients were randomly divided into three groups: dabigatran 110mg bid group, dabigatran 150mg bid group, and warfarin group, with warfarin dose adjusted according to the INR value (target value 2.0-3.0). The median follow-up time was 2.0 years. The results showed that the incidence rates of the primary efficacy endpoint (stroke or systemic embolism) were 1.53% in the dabigatran 110mg bid group, 1.11% in the dabigatran 150mg bid group, and 1.69% in the warfarin group. The incidence of the primary safety endpoint (major bleeding) was higher in the warfarin group than in the dabigatran 110mg group (P=0.003), but there was no statistically significant difference in the incidence of major bleeding between the dabigatran 150mg group and the warfarin group (P=0.31). In terms of the secondary endpoint of stroke incidence, the dabigatran 150mg group was lower than the warfarin group (P<0.001), but there was no reduction in stroke incidence in the 110mg group compared with the warfarin group (P=0.41). This article suggests that the efficacy of dabigatran (150mg bid) is superior to warfarin in AF patients, with a similar incidence of bleeding complications; dabigatran at a dose of 110mg bid reduces bleeding complications to some extent, with efficacy similar to that of warfarin. Dabigatran treatment does not require routine monitoring of coagulation function, but for elderly patients (aged ≥75 years), those with impaired renal function, frailty, and other high-risk factors for bleeding, the dose should be reduced and monitoring should be strengthened to avoid serious bleeding events.

Rivaroxaban

Rivaroxaban has a potent inhibitory effect on both free and bound factor Xa and prothrombinase complex, thereby significantly improving its anticoagulant efficacy. The ROCKET-AF study evaluated the efficacy of rivaroxaban in preventing thromboembolic events in patients with atrial fibrillation (AF). The study used a randomized, double-blind, double-dummy, clinically driven endpoint design to demonstrate that rivaroxaban is non-inferior to warfarin in preventing stroke events in patients with non-valvular AF. A total of 14,264 subjects were included, and the selected AF patients all had a history of stroke, transient ischemic attack, or systemic embolism, or had at least two independent risk factors for stroke (including chronic heart failure, hypertension, age ≥75 years, diabetes). The subjects were randomly assigned to receive rivaroxaban (20 mg once daily) or warfarin (with dose adjustment according to INR target range of 2.0-3.0). The study ended when a total of 405 primary endpoint events occurred. The results showed that compared with patients in the warfarin group with adjusted dose, patients in the rivaroxaban group had a 21% lower incidence of major efficacy endpoints (stroke and non-central nervous system embolism events) (P<0.001); the incidence of vascular death, stroke, and non-central nervous system embolism events in the rivaroxaban group was reduced by 14% (P=0.034), and the incidence of hemorrhagic stroke and non-central nervous system embolism events was significantly reduced. In terms of safety endpoints, the incidence of major bleeding and clinically relevant non-major bleeding events in the rivaroxaban group was comparable to that in the warfarin group (P=0.442). The incidence of intracranial hemorrhage in the rivaroxaban treatment group was reduced by 33% (P=0.019), the incidence of bleeding related to critical organ was reduced by 31% (P=0.007), and bleeding-related mortality was reduced by 50% (P=0.003). Existing evidence suggests that rivaroxaban is not inferior to, and may even be superior to warfarin in preventing thromboembolic events in patients with non-valvular AF, with better safety profile.

Apixaban

Apixaban is another direct factor Xa inhibitor. The AVERROES study showed that apixaban is more effective than aspirin in preventing stroke and systemic thromboembolic events in patients who are not suitable for warfarin therapy, without increasing the risk of serious bleeding. The study included 5,599 patients with atrial fibrillation (AF) who had at least one stroke risk factor and were not suitable for warfarin therapy. They were randomly assigned to receive either apixaban (5 mg, twice daily) or aspirin (81-324 mg/day) with an average follow-up period of 1.1 years. The results showed that the incidence of the primary endpoint (stroke and systemic embolism) in the apixaban group was 1.6% per year, significantly lower than that in the aspirin group (3.7% per year, P<0.001). The incidence of major bleeding was similar between the apixaban and aspirin groups (1.4% vs. 1.2% per year, P=0.57). Due to the significant benefit of apixaban over aspirin observed in the midterm analysis, the study was terminated early. The ARISTOTLE study used a double-blind, double-dummy, randomized controlled design to demonstrate that the efficacy of apixaban in preventing the primary composite endpoint (ischemic or hemorrhagic stroke and systemic embolism) was non-inferior to that of warfarin. The secondary objective was to investigate whether apixaban was more effective than warfarin in preventing the occurrence of the composite endpoint events consisting of ischemic or hemorrhagic stroke, systemic embolism, and all-cause death. A total of 18,201 patients with AF who were at high risk of stroke were enrolled and randomly assigned to receive apixaban (5 mg, twice daily, with a reduced dose of 2.5 mg, twice daily, in some patients) or dose-adjusted warfarin (target INR 2.0-3.0) for a minimum treatment period of 12 months. After an average follow-up of 1.8 years, compared with warfarin, apixaban reduced the risk of the primary composite endpoint by 21% (P<0.001), the risk of major bleeding by 31% (P<0.001), the risk of all-cause death by 11% (P=0.047), the risk of hemorrhagic stroke by 49% (P<0.001), and reduced the risk of intracranial hemorrhage by 58% (P<0.001). These results suggest that compared with dose-adjusted warfarin, apixaban can more effectively reduce the risk of stroke or systemic thrombosis, the risk of bleeding events, and the risk of all-cause death.

There is no doubt that the clinical application of novel oral anticoagulants provides a safe and effective new option for the prevention of thromboembolic complications in patients with atrial fibrillation (AF). However, due to the relatively short time since the introduction of these drugs, it is necessary to strengthen post-marketing safety monitoring and accumulate clinical experience. Additionally, to date, clinical research evidence on novel oral anticoagulants mainly comes from patients with non-valvular AF, and their value in patients with valvular AF and those undergoing valve replacement or repair surgery remains to be explored. In China (especially in economically underdeveloped areas), there are still a large number of patients with valvular AF, so warfarin still has an important clinical role and wide application value. At present, novel oral anticoagulants are mainly suitable for patients with non-valvular AF.

[1] Hu Daiyi, Guo Yifang, Y. (2012). Expert consensus on anticoagulant therapy for atrial fibrillation in China. [J].Cardiovascular Disease Prevention and Treatment, 12(3), 173-177. DOI: 10.3969/j.issn.1009-816X.2012.03.001.