Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. According to data published in 2004, the prevalence of atrial fibrillation was 0.77% among residents aged 30 to 85 years in China, with a prevalence of more than 30% among those aged 80 years or older [1,2]. Thromboembolic complications are the main cause of death and disability in AF, and stroke is the most common type of presentation. In patients with non-valvular AF, the annual incidence of ischemic stroke (approximately 5%) is two to seven times higher than in non-AF patients [3-6]. Prevention of new and recurrent strokes should be a major component of a comprehensive management strategy for patients with atrial fibrillation. A growing number of studies have confirmed that the rational application of anticoagulants in patients at increased risk of stroke can help to significantly reduce the incidence of ischemic stroke, yet most patients with AF in China do not receive anticoagulation therapy [1,2]. It is important to further increase the awareness of the dangers of AF and its complications and to enhance the prevention of thromboembolic complications (especially stroke) to improve the prognosis of patients and to reduce the socioeconomic and family burden associated with them. Several oral anticoagulants have been used in clinical practice, such as warfarin, dabigatran, rivaroxaban and apixaban. In order to promote and standardize anticoagulation therapy for patients with atrial fibrillation and reduce the incidence of thromboembolic complications in ischemic stroke, the Chinese Society of Cardiovascular Diseases, the Chinese Society of Cardiac Electrophysiology and Pacing, the Cardiovascular and Cerebrovascular Disease Committee of the Chinese Gerontological Society, the Rhythm Branch of Chinese Biomedical Engineering, the Evidence-Based Medicine Committee of the Chinese Physicians Association, and the Arrhythmia Alliance (China) have organized domestic experts to develop this expert consensus. This expert consensus has been developed.
1. Risk stratification of stroke and thromboembolism in patients with atrial fibrillation and principles of anticoagulation therapy
Appropriate anticoagulation therapy is an effective measure to prevent thromboembolic events in patients with atrial fibrillation, but at the same time it increases the risk of bleeding complications. Therefore, the benefit-risk ratio should be assessed before determining whether a patient is suitable for anticoagulation, and anticoagulation should be initiated only if the benefit of preventing thromboembolic events clearly outweighs the risk of hemorrhagic complications. The level of risk of ischemic stroke in patients with atrial fibrillation is closely related to their baseline characteristics, and risk stratification of patients based on baseline characteristics is the basis for the development of a proper anticoagulation strategy [7]. Currently, the CHADS2 scoring system is the most widely used clinical assessment tool, and its scoring method is shown in Table 1 [8]. As the CHADS2 score increases, the risk of future ischemic stroke in patients with atrial fibrillation gradually increases. In the absence of contraindications, all patients with atrial fibrillation with a CHADS2 score ≥2 should undergo long-term oral anticoagulant therapy. Patients with a CHADS2 score of 1 may be treated with aspirin (100 mg-300 mg, qd), and some patients may be considered for oral anticoagulation, while those with a CHADS2 score of 0 generally do not require anticoagulation.
Although there is conclusive research evidence that standardized anticoagulation for patients with atrial fibrillation at increased risk of thromboembolic events can significantly improve patient prognosis, most patients with atrial fibrillation in China are not treated with anticoagulants. And among patients on warfarin, most are not systematically monitored for international normalized ratio (INR), or INR remains ineffectively low (1.3-1.5). The reasons for this situation are manifold, among which the clinicians’ lack of awareness of the dangers of thromboembolic complications and their excessive concern about the increased risk of bleeding associated with conventional anticoagulant warfarin therapy are probably the main reasons. In fact, the benefits of anticoagulation in patients with atrial fibrillation far outweigh the risks of complications associated with anticoagulation therapy, provided that the relevant guidelines are followed and the indications are properly grasped and coagulation function is monitored as required.
2. Anticoagulation in patients with atrial fibrillation
2.1 Application of warfarin in anticoagulation therapy in patients with atrial fibrillation
Warfarin has been widely used in clinical practice for more than 60 years and has been playing an important role in the prevention of ischemic stroke in patients with atrial fibrillation. The drug exerts its anticoagulant effect by reducing the synthesis of coagulation factors II, VII, IX & X, among others. The full anticoagulant effect can only be achieved when all vitamin K-dependent coagulation factors are inhibited, so the maximum efficacy of warfarin is mostly achieved after 4-5 days of continuous dosing, and its anticoagulant effect disappears completely only after 5-7 days of discontinuation.
2.1.1 Research evidence
Several randomized clinical studies to date have demonstrated the role of warfarin in the primary and secondary prevention of stroke in patients with atrial fibrillation, showing that long-term warfarin therapy for patients with moderate-to-high-risk atrial fibrillation, with close monitoring of the INR, is effective in reducing the risk of ischemic stroke and is significantly more effective than placebo, aspirin, and aspirin combined with clopidogrel [9-11]. A meta-analysis of available studies showed [12] that warfarin treatment reduced the relative risk of stroke by 64% and the absolute risk of stroke by 2.7% per year in patients with atrial fibrillation. When only ischemic stroke was calculated, application of dose-adjusted warfarin treatment reduced the relative risk by 67% and the benefit was of the same magnitude in preventing initial and recurrent strokes. Warfarin treatment resulted in a significant 26% reduction in all-cause mortality with a low incidence of intracranial hemorrhage. This meta-analysis also found that interruptions in warfarin therapy or inadequate anticoagulation intensity in patients with atrial fibrillation significantly increased the risk of stroke.
2.1.2 Dosing regimen
Although guidelines such as the US recommend a starting therapeutic dose of warfarin of 5 mg/d-10 mg/d [13], the warfarin dose required to achieve the INR target in our population may be lower than in patients in Europe and the US due to racial and weight differences, so warfarin therapy should be applied starting at a lower dose (e.g., 1.5 mg/d-3.0 mg/d). If the INR does not reach the target at the initial dose, the INR can be gradually increased in the range of 1.0mg/d-1.5mg/d and continuously tested until it reaches the target value. Special populations (e.g., elderly, frail, malnourished, heart failure, liver disease, recent surgical treatment, or those taking drugs that potentiate the effects of warfarin) should start at lower doses (e.g., <1.5 mg/d).
During the course of warfarin therapy, the INR should be monitored periodically and the warfarin dose should be adjusted accordingly to control the INR between 2.0 and 3.0. Although the above target INR values are mainly derived from the results of clinical studies in Europe and the United States, there is no evidence that Chinese patients need to adopt a lower INR target value. If the INR does not reach the above range, it may not be effective in preventing thromboembolic events due to insufficient anticoagulant effect. Some authors have suggested that a lower INR target value (1.8-2.5) is appropriate for warfarin therapy in elderly patients, but evidence from large clinical studies is lacking for this view. Cohort studies suggest that patients with atrial fibrillation treated with warfarin have a 2-fold increased risk of stroke with an INR in the range of 1.5-2.0. Therefore, this consensus recommends that older patients should adopt the same INR target values as the general adult population (2.0-3.0).
The frequency of INR monitoring should be patient-specific. At the beginning of warfarin treatment, INR should be tested at least every 3-5 days, and after the INR reaches the target value and the warfarin dose is relatively fixed, testing every 4 weeks is sufficient. If the patient is treated with drugs that may affect the effect of warfarin or if other disorders occur during the course of warfarin therapy, the frequency of testing should be increased and the warfarin dose should be adjusted as appropriate. Common drugs that enhance the anticoagulant effect of warfarin include: antiplatelet agents, NSAIDs, quinidine, chloral hydrate, chloramphenicol, promethazine, cimetidine, etc. Some broad-spectrum antibacterial agents can enhance the effect of warfarin by reducing the synthesis of vitamin K. Common drugs that reduce the anticoagulant effect of warfarin include: phenobarbital, phenytoin sodium, vitamin K, estrogen, acid reducers, laxatives, rifampin, chlorothiazide, spironolactone, etc. Some Chinese herbs (e.g. Salvia, Ginseng, Angelica, Ginkgo, etc.) can have a significant effect on the anticoagulant effect of warfarin, so monitoring should also be enhanced when receiving concurrent herbal therapy. Some foods (e.g. grapefruit, mango, garlic, ginger, onion, kelp, cauliflower, kale, carrot, etc.) may also enhance or diminish the anticoagulant effect of warfarin and should be monitored during the course of medication.
2.1.3 Management of increased INR or occurrence of bleeding complications
Patients with an INR higher than the target value or bleeding complications during warfarin therapy should be actively managed. See Table 2 for specific management.
2.1.4 Contraindications
Warfarin therapy is contraindicated in the following cases: perioperative (including ophthalmic and oral surgery) or trauma; significant hepatic and renal impairment; moderate to severe hypertension (blood pressure ≥ 160/100 mmHg); coagulation disorders with bleeding tendency; active peptic ulcer; pregnancy; other bleeding disorders.
2.1.5 Limitations
Although the anticoagulant effect of warfarin is positive, there are some limitations of this drug. First, the extent to which coagulation mechanisms are affected by warfarin application varies widely and unpredictably between individuals, resulting in a wide range of variability in its effective dose. Second, the anticoagulant effect of the drug is susceptible to the effects of various foods and drugs, and frequent monitoring of coagulation and timely adjustment of drug doses are required during the course of administration, which can affect patient compliance with long-term therapy. Establishing a sound atrial fibrillation clinic or anticoagulation clinic with experienced specialists to systematically manage patients with atrial fibrillation receiving anticoagulation therapy can help to overcome its limitations to a certain extent.
2.1.6 Assessment of bleeding risk when applying oral anticoagulants
Anticoagulation therapy can increase the risk of bleeding complications in patients, so attention should be paid to assessing patients’ bleeding risk before and during treatment and determining the appropriate treatment plan based on the results of the assessment. There are several assessment methods used in clinical practice, among which the HAS-BLED scoring system is considered to be the easiest and most reliable scheme (Table 3). Patients with a score of 0 to 2 are considered to be at low risk of bleeding, and a score of ≥3 indicates an increased risk of bleeding.
It should be noted that patients at increased risk for bleeding tend to be at increased risk for thromboembolic events, and the static benefit of anticoagulation may be greater in these patients. Therefore, anticoagulant therapy should be administered as long as the patient has an indication for anticoagulation (CHADS2 score ≥2), and an increased HAS-BLED score should not be considered a contraindication to anticoagulation. Care should be taken to screen for and correct reversible factors that increase the risk of bleeding in such patients, and further intensive monitoring is required. The initial dose of warfarin therapy should be lower (1.0 mg/d-1.5 mg/d) and the frequency of monitoring coagulation markers should be increased. The INR needs to be tested every 1-2 days when starting warfarin therapy or during dose adjustment, and every 2 weeks after the INR reaches the standard.
2.2 Immediate detection of INR and patient self-management
Monitoring INR as required is an important guarantee of safe and effective anticoagulation therapy for patients with atrial fibrillation. At present, INR testing for patients with AF in China is mainly done in the central laboratory of the hospital. Although this model can ensure the quality of monitoring, it affects patient compliance to a certain extent because of the more complicated process, long waiting time, and the need to use venous blood specimens and other limitations. Recently, China began to introduce the point-of-caretest (POCT) technology, which is easy to operate and requires only a drop of finger blood to report test results instantly, greatly simplifying the testing process of anticoagulation therapy and providing convenience for rapid outpatient and emergency testing of INR as well as home monitoring of patients. Clinical studies have shown that the application of POCT technology for home self-monitoring in patients taking warfarin is equally effective compared with monthly high-quality clinical testing [14].
The standardized POCT technique is essential to ensure the reliability of the test results, so the necessary technical training should be provided to the users of the POCT instrument to ensure the standardization of its operation. If abnormally high or low POCT results are found, it is recommended that venous blood be collected in a central hospital laboratory to review the test results and make the necessary adjustments to the anticoagulation regimen as appropriate.
Experience in Europe and the United States has shown that the establishment of specialized atrial fibrillation clinics or anticoagulation clinics is an effective measure to improve anticoagulation coverage and prevent thromboembolic complications in patients with atrial fibrillation. At present, some large hospitals in China have made useful attempts and explorations in this regard, and achieved better results, which is worth promoting in large and medium-sized hospitals in China.
2.3 The role of aspirin in the prevention of thromboembolic events in patients with atrial fibrillation
There has been controversy about the value of aspirin for thromboembolic events in patients with atrial fibrillation. Although some authors have suggested that aspirin therapy may be considered as an option for those with a low risk of thrombosis (CHADS2 score 0-1), this suggestion lacks sufficient evidence. A new large cohort study including 132,372 patients with non-valvular atrial fibrillation suggested that aspirin, either alone or in combination with warfarin, did not have significant antithrombotic efficacy but increased the risk of bleeding [15]. Therefore, the role of aspirin in the prevention of thrombotic events in patients with atrial fibrillation remains to be further explored.
Anticoagulation in special populations
Current research evidence on anticoagulation in special populations is mainly from clinical trials on warfarin, and there is a lack of large clinical studies on new oral anticoagulants in this area. Referring to the 2010 European guidelines for the treatment of atrial fibrillation [7], the following recommendations for anticoagulation in special populations are made.
3.1 Perioperative anticoagulation
Patients with atrial fibrillation undergoing warfarin therapy need to be temporarily discontinued before surgery or interventional procedures and heparin applied as transitional therapy. For non-emergency procedures, warfarin generally needs to be discontinued about 5 days before surgery (about 5 half-lives) to reduce the INR to below 1.5. If the INR is >1.5 but the patient requires early surgery, the patient may be given a small oral dose (1-2 mg) of vitamin K to bring the INR back to normal as soon as possible. Anticoagulation in the perioperative period in patients with atrial fibrillation who have implanted mechanical heart valves or other thrombotic risk factors is controversial, and it is generally accepted that warfarin should be discontinued and transitional anticoagulation with low molecular weight heparin or normal heparin should be used.
3.2 Stable angina and peripheral arterial disease
The optimal anticoagulation strategy for patients with atrial fibrillation in combination with stable angina pectoris, carotid atherosclerotic disease, or peripheral arterial disease has yet to be explored. Although some authors suggest combining antiplatelet agents (especially aspirin) with warfarin for such patients, available studies suggest that adding aspirin to warfarin therapy does not further reduce the incidence of stroke and myocardial infarction, but significantly increases the risk of bleeding events. Warfarin alone for secondary prevention in patients with stable coronary artery disease is at least as effective as aspirin, and therefore warfarin-only therapy is recommended for such patients.
3.3 Acute coronary syndromes and/or percutaneous coronary interventions
The application of dual antiplatelet therapy (aspirin plus clopidogrel; 4 weeks for bare metal stents and 6-12 months for drug-eluting stents) in patients with unstable angina and post-coronary stenting significantly reduces the risk of adverse cardiovascular events. When these conditions are combined in patients with atrial fibrillation, the addition of dual antiplatelet therapy to warfarin therapy may also reduce the incidence of thromboembolic events. Available evidence suggests that the short-term (e.g., 4 weeks) addition of warfarin does not significantly increase the risk of bleeding events compared with dual antiplatelet agents alone, with an acceptable benefit/risk ratio, but the safety of long-term triple antithrombotic agents remains to be demonstrated. Patients with atrial fibrillation who have a bare metal stent may be treated with triple antithrombotic therapy for a short period of time (4 weeks) followed by warfarin and an antiplatelet agent (aspirin or clopidogrel), and after 12 months, if the patient is stable, anticoagulation with warfarin only, as is the case in patients with stable coronary artery disease. Drug-eluting stents should be followed by longer triple antithrombotic therapy (sirolimus, everolimus, and tacrolimus-eluting stents should be treated for ≥3 months, and paclitaxel-eluting stents should be treated for at least 6 months), followed by warfarin plus clopidogrel (75 mg/day) or aspirin (75-100 mg/day), combined with a proton pump inhibitor or H2 receptor antagonist if necessary. Warfarin anticoagulation alone may be applied after 12 months if the disease is stable.
If not contraindicated, patients with non-ST elevation myocardial infarction should be treated with dual antiplatelet therapy with aspirin in combination with clopidogrel. Concomitant anticoagulation is also indicated if the patient has atrial fibrillation and is at moderate to high risk of stroke. Patients in the acute phase may be treated with aspirin, clopidogrel, regular or low molecular heparin, or bivalirudin and/or glycoprotein IIb/IIIa inhibitors, followed by triple antithrombotic therapy (warfarin, aspirin and clopidogrel) for at least 3-6 months. If the patient is at low risk of bleeding and high risk of thromboembolism, warfarin with clopidogrel (75 mg/day) or aspirin (75-100 mg/day plus gastric mucosal protector) may be applied for 12 months. Thereafter warfarin alone is applied for long-term treatment.
Acute ST-segment elevation myocardial infarction requires a combination of aspirin, clopidogrel, and heparin. When patients have a high thrombotic load, bivalirudin or glycoprotein IIb/IIIa inhibitors may be given temporarily. Because this combination antithrombotic therapy can significantly increase the risk of bleeding, glycoprotein IIb/IIIa inhibitors or bivalirudin should not be routinely used at INR >2. The principles of medium- and long-term antithrombotic therapy in such patients are the same as for non-ST elevation myocardial infarction.
3.4 Acute ischaemic stroke
To date, there are few studies on antithrombotic therapy in the acute phase of ischemic stroke. Acute stroke is often the first presentation in patients with atrial fibrillation and the risk of stroke recurrence is highest in the first 2 weeks after cardiogenic stroke. However, anticoagulation during the acute phase of stroke increases the risk of intracranial hemorrhage or post-infarction bleeding, so antithrombotic therapy is not recommended for patients with ischemic stroke within 2 weeks of onset. Antithrombotic therapy should be initiated after 2 weeks of onset if there are no contraindications, and the principles of treatment are the same as for patients with general atrial fibrillation.
3.5 Atrial flutter
Retrospective studies have shown that patients with atrial flutter are at the same risk of thromboembolic complications as patients with atrial fibrillation and should therefore be managed according to the same principles of antithrombotic therapy as patients with atrial fibrillation.
3.6 Atrial fibrillation resuscitation
In patients with atrial fibrillation >48 hours or of unknown duration, transesophageal ultrasound is recommended for the presence of left atrial or auricular thrombus before elective cardioversion is proposed. If transesophageal ultrasound is not available, antithrombotic therapy with dose-adjusted warfarin (INR 2.0-3.0) should be administered for at least 3 weeks. Because left atrial dysfunction (atrial stenosis) is often present after resuscitation, patients are at significantly increased risk of intra-atrial thrombosis and should continue anticoagulation for approximately 4 weeks after resuscitation. Patients with atrial fibrillation episodes <48 hours can be directly cardioverted with concomitant common heparin for thromboprophylaxis. Oral anticoagulation should be started after cardioversion and continued for life in patients with high risk factors for stroke, but not routinely in those without high risk factors for thromboembolism. Cardioversion should be performed immediately if AF occurs >48 hours and is associated with hemodynamic instability (angina, myocardial infarction, shock, or pulmonary edema) and should be preceded by heparin therapy and followed by oral anticoagulant therapy. The duration of oral anticoagulation therapy (4 weeks or lifetime) depends on whether the patient has high risk factors for stroke.
4. Conclusion
Stroke and other thromboembolic complications are the main cause of death and disability in patients with atrial fibrillation, and reasonable anticoagulation therapy is important to improve the quality of life and long-term prognosis of patients with atrial fibrillation. Although relevant guidelines at home and abroad recommend thromboprophylaxis for patients with high-risk atrial fibrillation, most patients have not been treated accordingly so far, therefore, in future clinical work, efforts should be made to strengthen standardized anticoagulation therapy for patients with atrial fibrillation to reduce the risk of thromboembolic events. The clinical application of new oral anticoagulant drugs will provide new tools for the prevention of thromboembolic complications in patients with atrial fibrillation. These drugs have the advantages of easy administration, stable pharmacokinetic properties, no need for routine monitoring of coagulation indexes, and less influence by food and other drugs, which will definitely play a positive role in improving the coverage and compliance of anticoagulation therapy in patients with atrial fibrillation.