On March 21, the 2024 Atrial Fibrillation Clinical Standardized Diagnosis and Treatment Continuing Education Project Conference launched by Beijing Zhongkang Union Public Welfare Fund was successfully held. The conference was chaired by Professor Li Guangping from the Second Hospital of Tianjin Medical University and Professor Luo Xinping from Huashan Hospital Affiliated to Fudan University, and Professor Lv Qiang from Anzhen Hospital Affiliated to Capital Medical University, Professor Zhou Genqing from the First People's Hospital Affiliated to Shanghai Jiao Tong University, and Professor Zhang Zhihui from the Third Xiangya Hospital of Central South University participated in the sharing, mainly discussing the standardization of anticoagulation of atrial fibrillation.
Pay attention to the latest frontiers and decipher anticoagulation in cancer patients
Anticoagulation in cancer patients belongs to the category of oncologic cardiology, which involves anticoagulation therapy for tumor complicated with atrial fibrillation and anticoagulation for the prevention and treatment of tumor-associated venous thromboembolism (VTE), both of which focus on the application of non-vitamin K antagonist oral anticoagulants (NOACs). Professor Lv Qiang summarized the previous literature and the results of new clinical studies, and further supported or clarified the key points of anticoagulation in the current medical guidelines.
Anticoagulation for stroke/embolization prevention and treatment in patients with tumors and atrial fibrillation
Atrial fibrillation is an independent risk factor for an increased risk of stroke in cancer patients. Both the 2021 EHRA guideline "Anticoagulation Management in Patients with Tumors and Atrial Fibrillation"1 and real-world studies2 support NOACs as the preferred practice for anticoagulation in patients with tumors and atrial fibrillation. In a real-world study in Taiwan, the efficacy and safety advantages of edoxaban over warfarin atrial fibrillation anticoagulation were not affected by the presence or absence of tumor, and edoxaban significantly reduced the risk of all-cause death, ischemic stroke/systemic embolism, and gastrointestinal bleeding, as well as the risk of congestive heart failure and Alzheimer's disease3. The tumor subgroup analysis of the ENGAGE AF-TIMI 48 clinical study also confirmed that the efficacy of edoxaban compared with warfarin in combination with tumors and the safety ratio were comparable: in each efficacy endpoint, the combined tumor did not significantly affect the anticoagulation efficacy of edoxaban in patients with atrial fibrillation (P interaction ≥0.09), and compared with warfarin/no tumor, the use of edoxaban in patients with tumors and atrial fibrillation showed higher benefits of multiple efficacy events, reducing myocardial infarction, stroke/SEE, ischemic stroke, MACE, risks such as cardiovascular death; In terms of the risk of various types of bleeding at the safety endpoint, the safety of edoxaban in patients with atrial fibrillation was not significantly affected by the concomitant tumor (P interaction ≥0.06), and the bleeding risk of edoxaban in patients with tumor and atrial fibrillation was not significantly increased compared with that without tumor, and there was no significant difference with warfarin4.
图1. ENGAGE AF-TIMI 48肿瘤亚组疗效
图2. ENGAGE AF-TIMI 48肿瘤亚组安全性
When the number of combination drugs ranges from 0-2 to 3-5, the blood concentration changes less, less metabolized by CYP enzymes, and has fewer potential drug interactions, which is suitable for patients receiving antineoplastic drug therapy5.
In the 2022 ESC oncocardiology guideline 6, TIBP structured anticoagulation regimens are recommended for anticoagulation in patients with tumors and atrial fibrillation, with T being a stroke/thromboembolism risk assessment, B being a bleeding risk assessment, I being a drug-drug interaction assessment, and P being a patient preference assessment. Long-term anticoagulation management is recommended for men with a CHA2DS2-VASc score of 2 or more or women with a score of 3 or more, and long-term anticoagulation may also be considered for patients with a score of 1, and anticoagulation based on bleeding risk assessment in patients with a score of 0. NOACs may be preferred as stroke prophylaxis over low molecular weight heparin (LMWH) and vitamin K antagonists (VKAs) in patients without high bleeding risk, significant drug interactions, or severe renal insufficiency (except in patients with mechanical valve replacement or moderate-severe mitral stenosis).
Figure 3. The 2022 ESC oncocardiology guidelines recommend anticoagulation in patients with tumors and atrial fibrillation
Anticoagulation for the prevention and treatment of tumor-related venous thromboembolism
Compared with the general population, the risk of VTE is 1.34 to 4.16 times higher7, and the tumor type, location, stage, time to diagnosis, comorbidities and certain cancer treatments all affect tumor VTE, and anticoagulation therapy is more complex. For patients with tumor VTE, the anticoagulation of NOACs represented by edoxaban showed non-inferiority or superiority in efficacy and safety compared with LMWH and warfarin: a multicenter, retrospective, large-sample COMMAND VTE registry study in Japan showed that compared with warfarin, the hospitalization rate of VTE patients treated with NOACs anticoagulation was 69% vs 80% (P=0.006), and the overall risk of major bleeding was 13.7% vs 12.1% (P=0.07) was not significantly increased. It also had significantly lower 5-year VTE recurrence rate (P<0.001) and major bleeding incidence (P=0.04)8. In a Hokusai-VTE tumor subgroup analysis, edoxaban significantly reduced the risk of VTE recurrence compared with warfarin, with HR 0.53 (95%CI 0.28-1.00), P = 0.0007, and major bleeding or CRNM bleeding, HR 0.64 (95%CI 0.45-0.92), P = 0.0179.
Figure 4. Recurrence of VTE and incidence of major bleeding
Prolonged/continuous anticoagulation is a hot topic of clinical concern. The ONCO DVT study in Japan10 revealed for the first time that edoxaban long-term (12 months) anticoagulation can improve the benefit of deep vein thrombosis (DVT) in tumors, which was specially reported on the official website of the ESC2023 conference. In the study, 604 patients with active tumors newly diagnosed with solitary distal DVT were divided into 12-month treatment (n=296) and 3-month treatment (n=305), and the risk of symptomatic VTE recurrence or VTE-related death was significantly reduced (OR, 0.13) by edoxaban anticoagulation at 12 months, but the risk of major bleeding was not significantly increased (OR, 1.34).
Figure 5. Symptomatic recurrence of VTE or VTE-related death
Figure 6. Risk of major bleeding
Keep up with the frontier and discuss anticoagulation in special populations
Professor Zhou Genqing gave a detailed interpretation of anticoagulation in patients with diabetes mellitus and cardiomyopathy combined with atrial fibrillation from the perspective of multidisciplinary guidelines, as well as special populations in the latest research progress in 2023.
Comorbid diabetes does not affect the efficacy or safety of NOACs
Diabetes mellitus is an independent risk factor for atrial fibrillation, which significantly affects the clinical outcome of patients. The 2023 ESC Guidelines for the Management of Cardiovascular Disease in Diabetic Patients with Diabetes indicate that NOAC anticoagulation is the preferred choice for patients with diabetes and atrial fibrillation11. Data from pooled analysis of eight studies, four RCT studies and four observational studies, comparing the efficacy and safety of NOACs and VKAs in patients with and without diabetes mellitus, showed that the P value of the interaction was > 0.0512.
Figure 7. Comorbid diabetes did not affect the efficacy or safety outcomes of NOACs
In the subgroup analysis of the diabetic population in the ENGAGE AF-TIMI 48 study, the P value of the interaction in the efficacy of edoxaban was also greater than 0.05, indicating that the presence or absence of diabetes did not affect the effectiveness of edoxaban in patients with atrial fibrillation. In addition, edoxaban significantly reduces the risk of major bleeding, fatal, or life-threatening bleeding in patients with diabetes and atrial fibrillation13.
Figure 8. Endoxaban is also effective in patients with atrial fibrillation with diabetes mellitus and is comparable to warfarin
Figure 9. Edoxaban significantly reduces the risk of major bleeding, fatal or life-threatening bleeding
Guidelines recommended for cardiomyopathy with atrial fibrillation
The 2023 ESC Guidelines for the Management of Cardiomyopathy recommend that for all patients with hypertrophic cardiomyopathy (HCM) or cardiac amyloidosis with atrial fibrillation or atrial flutter (unless contraindicated), and for patients with dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC) with atrial fibrillation or atrial flutter and a CHA2DS2-VASc score of ≥2 (males) or ≥3 (females), Oral anticoagulation is recommended to reduce the risk of stroke and thromboembolic events14.
Recent advances in anticoagulation in special populations
In patients with atrial fibrillation with bioprosthetic heart valves, the results of a systematic review and meta-analysis showed a 9% reduction in the relative risk of death with NOACs (HR 0.91; P = 0.0068; 95% CI 0.85-0.97) and a 21% relative risk of major bleeding (HR 0.79; P = 0.0001; 95% CI 0.73-0.85)15. Oral anticoagulant therapy (OAC) therapy is not ideal in patients with atrial fibrillation after coronary artery bypass grafting, and antithrombotic therapy needs to be improved, particularly in patients with a history of myocardial infarction16. In patients on antiplatelet therapy, NOAC therapy is more effective than warfarin, with an absolute lower risk of intracranial hemorrhage (ICH)17.
In patients with atrial fibrillation with a prior history of ischemic stroke or transient ischemic attack (TIA), the ENGAGE AF-TIMI 48 study showed that edoxaban was as effective as warfarin in preventing stroke and hemorrhagic events, but was safer18.
Figure 10. Proportion of patients with stroke/systemic embolism
Figure 11. Proportion of patients with intracranial hemorrhage
Heart failure combined with atrial fibrillation, how to choose anticoagulation?
Professor Zhang Zhihui pointed out that atrial fibrillation and heart failure affect each other and cause and effect each other. The coexistence of the two can accelerate disease progression and worsen prognosis. At present, it is estimated that there are more than 4 million patients with atrial fibrillation and heart failure in mainland China, 21%~68% of patients with atrial fibrillation with heart failure in clinical trials19, and 34.1% of patients with chronic heart failure in clinical trials with atrial fibrillation20. Heart failure is an independent risk factor for the development of atrial fibrillation and significantly increases the risk of atrial fibrillation. Heart failure significantly increases the risk of atrial fibrillation by 4.4 times in women and 3.6 times in men21. The coexistence of atrial fibrillation and heart failure accelerates disease progression and worsens prognosis22,23.
Guidelines at home and abroad unanimously recommend that atrial fibrillation with heart failure require anticoagulation therapy, and NOACs should be preferred. The 2023 Chinese National Heart Failure Guidelines 24, 2021 Atrial Fibrillation: Current Understandings and Recommendations25 and the 2023 ACC Antithrombotic Therapy Guidelines for Atrial Fibrillation 26 recommend that patients with atrial fibrillation and heart failure should be treated with oral anticoagulation to prevent stroke recurrence. The 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure27 and the 2023 national heart failure guidelines28 unanimously recommend that patients with atrial fibrillation and heart failure should be preferably anticoagulated with NOACs. A meta-analysis of NOAC RCTs showed that NOACs were more effective and safer than warfarin in patients with atrial fibrillation with heart failure, with a 14%, 24%, and 57% reduction in the relative risk of stroke/systemic embolism, major bleeding, and intracranial hemorrhage, respectively.29
Figure 12. In patients with atrial fibrillation with heart failure, the efficacy and safety of NOACs are better than those of warfarin
Heart failure is an important risk factor in stroke risk scores, accounting for 1 point in both CHADS2 and CHA2DS2-VASc scores, and stroke risk scores in patients with atrial fibrillation and heart failure ≥ 1 30,31. Authoritative guidelines at home and abroad unanimously recommend that patients with atrial fibrillation and heart failure should be treated with oral anticoagulation to prevent stroke recurrence24-26. In a subgroup analysis of heart failure in the 32 ENGAGE TIMI AF study, edoxaban was comparable to warfarin in preventing stroke/systemic embolism as the primary efficacy endpoint.
Figure 13. The primary efficacy endpoint of edoxaban is similar to that of warfarin
Studies have shown that with the severity of heart failure and the deterioration of cardiac function, the risk of major bleeding, fatal bleeding, and gastrointestinal bleeding increases (P* trend <0.05)32. The incidence of hemorrhagic stroke in the edoxaban treatment group was lower than the trend of warfarin, and the safety profile was superior. Regardless of whether there is heart failure or not, edoxaban significantly reduced intracranial hemorrhage, and the risk of mild heart failure was reduced by 55% (P=0.001), 65% (P=0.026) in severe patients, and 49% (P=0.003) in patients without heart failure. The risk of major bleeding in patients with mild heart failure was significantly reduced by 21% (P=0.02). Significantly reduced the risk of fatal bleeding in patients with severe heart failure by 86%32.
Figure 14. The incidence of bleeding in edoxaban is lower than that of warfarin
Summary of the meeting
In this meeting, experts shared the latest guidelines and research progress on anticoagulation management in patients with tumor complicated with atrial fibrillation, tumor-related venous thromboembolism, diabetes mellitus with atrial fibrillation, cardiomyopathy with atrial fibrillation, and heart failure with atrial fibrillation.
At the end of the meeting, Professor Luo Xinping and Professor Li Guangping made a summary. Professor Luo Xinping discussed how to improve anticoagulation management, 40% of patients with atrial fibrillation are currently in neurology, more than 30% in cardiology, and more than 10% in other departments, so it is necessary to gather all departments in the atrial fibrillation center (every 1-2 months). At the same time, atrial fibrillation alliances can be established in different hospitals. In addition, for patients with tumors and VTE, early use of edoxaban can greatly reduce mortality; For patients with atrial fibrillation and heart failure, wall ablation should be done first, and such patients are more likely to develop atrial fibrillation and should be more aggressively anticoagulation. Professor Li Guangping concluded that although atrial fibrillation is a manifestation of heart disease, the cause of atrial fibrillation may involve multiple departments, and it is necessary to strengthen the construction of atrial fibrillation centers in hospitals, strengthen exchanges and cooperation between departments, and jointly do a good job in the standardized management of atrial fibrillation anticoagulation, so as to benefit patients.
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