Unresolved issues of anticoagulation in atrial fibrillation: age, BMI, reduced dose, and ethnicity

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Atrial fibrillation is associated with a considerable, but variable, risk of stroke in individual patients.1 Novel oral anticoagulants are protective and are therefore increasingly used in clinical practice2 and, with the experience gained in practice and in trials, comprehensive recommendations have been published.3–5 Nevertheless, important issues remain. For instance, the dose of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation may require reductions according to specific criteria. However, in pivotal trials, the numbers of patients receiving reduced dose regimens were small, thereby limiting the ability to draw meaningful conclusions. Thus, in their article entitled ‘Efficacy and safety of reduced-dose non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a meta-analysis of randomized controlled trials’, Robert P. Giugliano and colleagues from the TIMI Study Group, Brigham and Women’s Hospital in Boston, Massachusetts, USA6 report the results of their meta-analysis of contemporary trials. Rates of stroke or systemic embolism and major bleeding were higher in patients eligible for reduced dose NOACs than in those eligible for full dose NOACs. Compared with patients eligible for full dose, risks of stroke or systemic embolism and major bleeding were comparably lower with NOACs than with warfarin in patients eligible for reduced dose NOACs (Figure 1). Although the risk of ischaemic stroke with NOACs and with warfarin was similar, both doses of NOACs were associated with consistent reductions in risks of systemic embolism, haemorrhagic stroke, intracranial haemorrhage, and fatal bleeding. Thus, patients eligible for reduced dose NOACs were at higher risk of thrombo-embolic and haemorrhagic complications when treated with anticoagulants. The efficacy and safety of NOACs were preserved with appropriately reduced treatment doses. This highlights the importance of prescribing NOAC dose reductions for the right patient populations, a recommendation that is put into further perspective in a comprehensive Editorial by Dan Atar from the Oslo University Hospital in Norway.7 Comparative performance between reduced-dose non-vitamin K antagonist oral anticoagulants and full-dose non-vitamin K antagonist oral anticoagulants relative to warfarin. CI, confidence interval; NOAC, non-vitamin K antagonist oral anticoagulant; RR, risk ratio (from Wang K-L, Lopes RD, Patel MR, Büller HR, Tan DS-Y, Chiang C-E, Giugliano RP. Efficacy and safety of reduced-dose non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a meta-analysis of randomized controlled trials. See pages 1492–1500). As patients with atrial fibrillation get older and accumulate more comorbidities after the onset of atrial fibrillation, stroke risk should ideally be analysed using an assessment which considers incident comorbidities and the actual age when ischaemic stroke occurred. In their article ‘Age threshold for the use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation: insights into the optimal assessment of age and incident comorbidities’, Shih-Ann Chen and colleagues from the Taipei Veterans General Hospital in Taiwan assessed age treatment thresholds for the use of NOACs in 70 059 patients without or with only one comorbidity except for age and gender.8 The risks of ischaemic stroke in each age stratum for each comorbidity were analysed in three ways: (i) the conventional way (based on baseline risk factors and age); (ii) a dynamic method (patients were censored when new comorbidities occurred); and (iii) an ideal method (patients were censored when new comorbidities occurred and the stroke risk was related to the actual age when the stroke happened). The tipping point for the use of NOACs was set at a stroke risk of 0.9%/year. The conventional way overestimated the risk of ischaemic stroke compared with the dynamic or ideal assessment, with the incidence rate ratio of 1.64 for age, 1.24 for patients with hypertension, 1.20 for heart failure, 1.37 for diabetes mellitus, and 1.38 for vascular diseases. With heart failure, the tipping point (age 35 years) of NOACs is similar, irrespective of the methods used for stroke risk assessment. According to the results of the ideal assessment, the age thresholds for the use of NOACs for patients with hypertension, diabetes mellitus, and vascular diseases were 50, 50, and 55 years, respectively (Figure 2). Thus, age thresholds for the use of NOACs were different for patients having one additional risk factor beyond gender despite the same CHA2DS2-VASc score (one for males and two for females). This complex analysis is put into practical context in an educational Editorial by Samuel Goldhaber from the Harvard Medical School in Boston, Massachusetts, USA.9 According to the stroke risks we reported using the ‘ideal assessment’, NOACs should be considered for stroke prevention for AF patients aged 60 or above without other comorbidities. The age thresholds for the use of NOACs for AF patients having one additional risk factor beyond sex are 35, 50, 50 and 55 years for heart failure, hypertension, diabetes, and vascular diseases, respectively. AF, atrial fibrillation; NOACs, non-vitamin K antagonist oral anticoagulants (from Chao T-F, Lip GYH, Lin Y-J, Chang S-L, Lo L-W, Hu Y-F, Tuan T-C, Liao J-N, Chung F-P, Chen T-J, Chen S-A. Age threshold for the use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation: insights into the optimal assessment of age and incident comorbidities. See pages 1504–1514). Previous studies suggested that the risks of ischaemic stroke and bleeding in patients of Asian race with atrial fibrillation may be higher than those of non-Asians. In their article entitled ‘Clinical outcomes, edoxaban concentration, and anti-factor Xa activity of Asian patients with atrial fibrillation compared with non-Asians in the ENGAGE AF-TIMI 48 trial’, Robert P. Giugliano and colleagues from the TIMI Study Group, Brigham and Women’s Hospital in Boston, Massachusetts (USA) analysed clinical outcomes, edoxaban concentrations, and anti-factor Xa activity between 2909 Asians and 18 195 non-Asians.10 Compared with non-Asians, Asians were on average 2 years younger and 20 kg lighter. In the warfarin group, the adjusted risk for ischaemic stroke did not differ between the two groups; however, Asians treated with warfarin had a higher risk of intracranial haemorrhage, with a hazard ratio of 1.71. The trough edoxaban concentration and anti-factor Xa activity were 20–25% lower in Asians than in non-Asians. Compared with warfarin, higher dose edoxaban reduced intracranial haemorrhage while preserving stroke protection in both Asians and non-Asians. Two of three net clinical outcomes appeared to be more favourably reduced with edoxaban in Asians compared with non-Asians. Thus, compared with warfarin, higher dose edoxaban preserved the efficacy for stroke prevention and was associated with a more favourable safety for Asians, which may be due to the lower edoxaban concentration and anti-factor Xa activity. The manuscript is accompanied by an informative Editorial by Jan Steffel from the University Hospital Zurich in Switzerland.11 Whether or not and when anticoagulants should be stopped after injury12 or before a procedure13 with NOACs or vitamin K antagonists14 remains controversial. Indeed, although a recent expert consensus statement has recommended peri-procedural uninterrupted NOACs during catheter ablation of atrial fibrillation as a class I indication, there have been no clear randomized trials on that issue. In their article ‘When is it appropriate to stop non-vitamin K antagonist oral anticoagulants before catheter ablation of atrial fibrillation? A multicentre prospective randomized study’ Hui-Nam Pak and colleagues from the Yonsei University Health System in Seoul, Republic of South Korea and colleagues investigated the safety and efficacy of uninterrupted, procedure day single dose skipped, and 24-h skipped NOACs in patients undergoing atrial fibrillation ablation in a prospective, open-label, randomized multicentre trial involving 326 patients.15 Patients scheduled for catheter ablation were randomly assigned in a 1:1:1 to uninterrupted, procedure day single dose skipped, and 24-h skipped at three tertiary hospitals. Bridging with low molecular weight heparin was carried out in patients with persistent atrial fibrillation who were assigned to the 24-h skipped group. The intraprocedural heparin requirement was higher in the 24-h skipped group than the others, while the mean activated clotting time was comparable between the groups. The incidence of major bleeding up to 1 month after ablation and a post-procedural reduction in the haemoglobin levels did not significantly differ among the treatment groups or different NOACs and there were no fatal events or thrombo-embolic complications in all groups. Thus, in patients undergoing atrial fibrillation ablation, uninterrupted NOACs and single or double dose skipped NOACs had a comparable efficacy and safety, regardless of the type of NOAC. These clinically important findings are further discussed in a balanced Editorial by Jared T. Bunch from the Intermountain Medical Center in Murray, Utah, USA.16 Obesity and body mass and size affect both the occurrence of atrial fibrillation and plasma levels of anticoagulants.17,18 This was further investigated in the article entitled ‘Relationship between body mass index and outcomes in patients with atrial fibrillation treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial’ by Robert P. Giugliano and colleagues from the TIMI Study Group, Brigham and Women’s Hospital in Boston, Massachusetts, USA.19 The ENGAGE AF-TIMI 48 trial randomized 21 028 patients with atrial fibrillation to warfarin or edoxaban. Higher body mass indexes (BMIs) predicted lower risks of stroke and systemic embolism, with a hazard ratio of 0.88, ischaemic stroke or systemic embolism with a hazard ratio of 0.87, and death with a hazard ratio of 0.91. However, the risk of major or clinically relevant non-major bleeding also increased. Though edoxaban concentration and anti-factor Xa activity were similar across BMI groups, time-in-therapeutic range for warfarin improved significantly as BMI increased. The effects of edoxaban vs. warfarin on stroke/systemic embolic events (SEEs), major bleeding, and net clinical outcome were similar across BMI groups. Thus, in line with previous studies,20 an increased BMI is independently associated with a lower risk of stroke or systemic embolism, better survival, but an increased risk of bleeding with both edoxaban and warfarin. These provocative results are put into context in an interesting Editorial by Stefan Anker from the Charité Campus Virchow-Klinikum in Berlin, Germany.21 In patients undergoing percutaneous coronary intervention (PCI), the presence of atrial fibrillation makes the choice of the antithrombotic regimen challenging, mainly because of the increased bleeding risk. This issue is addressed in the article ‘Dabigatran dual therapy with ticagrelor or clopidogrel after percutaneous coronary intervention in atrial fibrillation patients with or without acute coronary syndrome: a subgroup analysis from the RE-DUAL PCI trial’ by Jonas Oldgren and colleagues from the Uppsala University Hospital in Sweden.22 In the RE-DUAL PCI trial, 2725 patients were randomized to dabigatran 110 mg or 150 mg with a P2Y12 inhibitor or to warfarin with a P2Y12 inhibitor and aspirin. The risk of major or clinically relevant non-major bleeding was reduced with both dabigatran dual therapies vs. warfarin triple therapy in patients with acute coronary syndromes (ACS), with a hazard ratio of 0.47 for 110 mg and 0.67 for 150 mg. For elective PCI, the corresponding values were 0.57 for 110 mg and 0.76 for 150 mg. The results were similar with ticagrelor or clopidogrel. Overall, dabigatran dual therapy was comparable with warfarin triple therapy for the composite endpoint of death, myocardial infarction, stroke, systemic embolism, or unplanned revascularization both in ACS and in elective PCI patients. Thus, the benefits of both dabigatran plus P2Y12 inhibitor dual therapy compared with warfarin triple therapy in reducing bleeding risks were consistent across subgroups of patients with or without ACS, and patients treated with ticagrelor or clopidogrel. These important results are compared with the previous literature in a comprehensive Editorial by Roxana Mehran from the Mount Sinai School of Medicine in New York, USA.23 This issue is complemented by various Discussion Forum contributions. In a first contribution, Paul Bamford and a colleague from the Gosford Hospital in Australia comment on the recently published paper ‘Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial’ by Jonathan P. Piccini from the Duke University Medical Center in Durham, North Carolina, USA.24,25 Piccini et al. respond convincingly in their own comment.26 In another Discussion Forum ‘Drug–drug interaction between levetiracetam and non-vitamin K antagonist anticoagulants’,27 Barbara Pelgrims and colleagues from UCB Pharma SA in Anderlecht, Belgium discuss issues of ‘The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation’.28 Jan Steffel, the first author of the EHRA Document, responds to this comment.29 A final Discussion Forum ‘Combination of non-vitamin K antagonist oral anticoagulants and antiepileptic drugs’ by Semiha Kurt from the Tokat Gaziosmanpasa Universitesi Tip Fakultesi in Turkey also refers to the Practical Guide.30 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet for help with compilation of this article.