{"doi":"10.1093/europace/euq427","title":"Chronic renal disease and stroke in atrial fibrillation: balancing the prevention of thromboembolism and bleeding risk","abstract":null,"journal":"Europace","year":2011,"id":686262,"datarank":0.5101796072493234,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.0,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":2556,"name":"G. Y. H. Lip","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Chronic renal disease and stroke in atrial fibrillation: balancing the prevention of thromboembolism and bleeding risk","abstract":"This editorial refers to ‘Warfarin in haemodialysis patients with atrial fibrillation: what benefit?’ by F. Yang et al., Europace 2010, 12(12):1666–1672 Atrial fibrillation (AF) confers a substantial risk of stroke and thromboembolism, and recent guidelines have advocated a risk factor-based approach to thromboprophylaxis.1 Common risk factors in everyday clinical practice have been investigated in datasets from clinical trials and cohort studies,2,3 and have been used to formulate various risk-stratification schemes, such as the CHADS2 [Cardiac Failure, Hypertension, Age, Diabetes, Stroke (Doubled)] score.4 Given the limitations of the latter and the non-inclusion of various ‘stroke-modifier’ risk factors,5 more comprehensive stroke-risk schemes such as the CHA2DS2-VASc [Cardiac Failure, Hypertension, Age ≥75 (Doubled), Diabetes, Stroke (Doubled)—Vascular disease, Age 65–74, and Sex category (Female)] score have been proposed.6 This comprehensive risk factor-based approach has been advocated in the 2010 European Society of Cardiology (ESC) guidelines on AF management.1 Even the CHA2DS2-VASc score has been (slightly) criticized for not including some risk factors associated with thromboembolism in non-valvular AF, such as cardiomyopathies (e.g. hypertrophic cardiomyopathy), infiltrative heart disease (e.g. amyloid), and renal failure. Conditions such as cardiomyopathy and amyloid are rare and while case reports and small series have suggested that such patients are at risk of stroke,7,8 they have not been specifically studied in the large randomized trials of stroke prevention in AF, to allow assessment of its predictive value for stroke on multivariate analysis. Another important consideration is the need for simplicity in any risk-stratification scheme and to have a risk score that at least can be used in everyday clinical practice, applicable to the majority of AF patients. Patients with chronic renal disease represent a complex management problem in relation to decision-making for thromboprophylaxis in AF. If these patients have severe renal impairment (e.g. creatinine clearance <30 mL/L, including those on dialysis), they have a very high risk of stroke (whether in AF or not), cardiovascular events (including myocardial infarction), death, and—especially if they are treated with oral anticoagulation (OAC)—bleeding.9–12 For example, in the cohort study by Chan et al.,12 with the use of warfarin among AF patients with end-stage renal disease (on haemodialysis), there was an increased risk for new stroke (hazard ratio 1.93; 95% CI 1.29–2.90), with the greatest risk in warfarin users who did not receive INR monitoring in the first 90 days of dialysis. In this issue of Europace, Yang et al.13 provide a comprehensive overview of the use of OAC (i.e. warfarin) in haemodialysis patients with AF. They conclude that patients on haemodialysis probably do not derive the same benefit from warfarin as the general AF population. Indeed, warfarin may even put the haemodialysis patients at increased risk of haemorrhagic stroke and possibly, ischaemic stroke. Also, Yang et al.13 remind us that warfarin increases the risk of major bleeding and has been associated with vascular calcification. While many clinicians would still anticoagulate the AF patient with chronic renal disease, Yang et al.13 even suggest that the routine use of warfarin in dialysis for stroke prevention should be discouraged, and therapy should only be reserved for haemodialysis patients at particularly high risk for thrombo-embolic stroke and if started, the patient should be very carefully reviewed and monitored. In the RELY (Randomized Evaluation of Long-term anticoagulant TherapY with dabigatran etexilate) trial comparing the direct thrombin inhibitor, dabigatran, against warfarin (INR 2–3), the beneficial effects of dabigatran 110 mg bid in reducing major bleeding by 20% in the overall trial was less apparent in subjects with moderate renal impairment (30–60 mL/L).14,15 Those with severe renal impairment (<30 mL/L) were excluded from the trial. In any case, dabigatran would not be useful in chronic renal failure patients undergoing haemodialysis as the drug would be removed from the system by haemodialysis. Other new OACs, such as the oral Factor Xa inhibitors that are at advance stages of investigation, such as rivaroxaban, apixaban, and edoxaban, have a degree of renal excretion—and in their Phase 3 trials, those with severe renal impairment are excluded.16 There is also a small dose adjustment for those with moderate renal impairment. One new oral Factor Xa inhibtor, betrixaban, would be of interest to those managing such patients. This drug has minimal renal excretion, and may potentially be able to be used in AF patients with renal impairment. One Phase 2 trial (EXPLORE-Xa) with betrixaban has been presented,17 but data from a Phase 3 trial that include sufficient numbers of patients with severe renal impairment would be needed. As discussed above, current comprehensive stroke-risk schemes that include the ‘common’ stroke risk factors seen in everyday practice, such as the CHA2DS2-VASc score, do not include chronic renal impairment (or reduced creatinine clearance) as a risk factor. Chronic renal disease also commonly coexists with age, hypertension, diabetes, heart failure, and vascular disease, which are individual stroke risk factors already contained within the CHA2DS2-VASc score. If renal dysfunction were to be formally added to the CHA2DS2-VASc score, a formal validation exercise would require a large prospective dataset of patients with chronic renal disease to determine the independent incremental stroke risk over the risk factors mentioned above. Also, given that the AF population is largely elderly, with multiple comorbidities and concomitant drug therapies that may influence renal function, those with ‘borderline’ moderate renal impairment (e.g. creatinine clearance 30–35 mL/L) would require close monitoring of their renal function especially during treatment with new OAC, such as dabigatran, rivaroxaban, and edoxaban, as if renal function deteriorates (and creatinine clearance falls below 30 mL/L, the usual cut-off level defining ‘severe renal impairment’), the patients may be at risk of bleeding. Clearly, these new OACs have removed the need for INR monitoring, but this was not meant to be substituted with creatinine clearance monitoring for those with borderline severe renal impairment. What could the future bring? Given that proteinuria is also associated with increased thrombo-embolic risk in AF18 and the increased stroke risk of patients with renal impairment—and notwithstanding the requirement for a major validation exercise with the associated caveats mentioned in the preceding paragraph—one possibility would be to informally make the ‘c’ (the ‘little c’ which is currently part of ‘Sc’ for sex category, i.e. female gender) in the CHA2DS2-VASc score to abbreviate for ‘creatinine clearance <30 mL/L or proteinuria’, and give this one extra point on the score. However, the decision on OAC would also need to take bleeding risk into consideration. Also, given the overview and conclusions by Yang et al.,13 the threshold for ischaemic stroke in those with chronic renal disease would probably need to be higher to require OAC, and a bleeding risk assessment regularly needed. In the ESC guidelines,1 the HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65), Drugs/alcohol] score is recommended as an easy, practical way to assess bleeding risk, whereby a HAS-BLED score of ≥3 indicates ‘high-risk', and caution and/or regular review is recommended. However, ‘abnormal renal function’ scores one point on the HAS-BLED score, and many stroke risk factors are also risk factors for bleeding. Also, the HAS-BLED score has not been validated in patients with chronic kidney disease. One possible proposal is that for patients with chronic kidney disease, OAC (essentially warfarin) should be given for those at high stroke risk (e.g. a CHA2DS2-VASc score of ≥2) and that a HAS-BLED score of ≥3 would indicate regular review and follow-up is necessary. This is in contrast to the current ESC guidelines, where OAC is preferred for those with one or more stroke risk factors (i.e. CHA2DS2-VASc score of ≥1).1 A suggested schema is shown in Figure 1 (modified from19), and given the lack of large prospective clinical trial data for the new agents (e.g. dabigatran, apixaban, etc.) in severe renal impairment, we should continue to use warfarin (perhaps target INR 2.0–2.5) with careful INR monitoring, to ensure excellent anticoagulation control (with a high time in therapeutic range), and to minimize stroke and bleeding risks.20 Interestingly, dabigatran was recently approved in the United States at a dose of 75mg BID for patients with a creatinine clearance of 15–30 mL/min, despite the absence of a prospectrive controlled trial testing this dose. There would also need to be consideration of prior OAC exposure and tolerability.19 Algorithm for oral anticoagulation therapy for stroke prevention in patients with atrial fibrillation and chronic renal disease. Oral anticoagulation (OAC), for example, with Vitamin K antagonists (VKAs, target INR 2–2.5) but new drugs which may be viable alternatives to the VKAs could ultimately be considered. Asterisk (*) signifies that risk factors for stroke and thromboembolism could be assessed using the CHA2DS2-VASc score, although the real stroke risk is likely to be much higher than reported in cohorts with no renal failure. If patients have already been taking OAC (e.g. for >3 months) with no bleeding complications, these patients probably represent a patient group that would ‘tolerate’ OAC with a lower bleeding risk. Plus (+) signifies that bleeding risk could be assessed using a validated scoring system (e.g. the HAS-BLED score) although the real bleeding risk may be higher than that reported in cohorts with no renal failure. A HAS-BLED score of ≥3 indicates the need for caution and/or regular review of the patient. Such an (informal) management proposal would really need validation in multiple prospective independent cohorts, before formal incorporation into guidelines—and not beforehand. Ultimately, new OAC such as betrixaban may offer an additional option in management, pending proof from prospective outcome trials, but until then, a delicate balance will remain between stroke and thrombembolism prevention, and bleeding risk with OAC in patients with severe renal impairment. Conflict of interest: none declared.","is_dataset_classified":null,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21138929","pmcid":null,"openalex_id":"https://openalex.org/W2077899415","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2012,"count":6},{"year":2013,"count":7},{"year":2014,"count":5},{"year":2016,"count":3},{"year":2017,"count":2},{"year":2018,"count":1},{"year":2021,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"http://academic.oup.com/europace/article-pdf/13/2/145/7276814/euq427.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/europace/euq427","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/21138929","host_type":"repository"},{"url":"https://research.birmingham.ac.uk/en/publications/fc92cbe0-3bc4-468e-b49a-6bc7c934f9ed","host_type":"repository"}],"fields_of_study":["Atrial Fibrillation Management and Outcomes","Acute Ischemic Stroke Management","Venous Thromboembolism Diagnosis and Management"],"mesh_terms":["Anticoagulants","Atrial Fibrillation","Chronic Disease","Renal Dialysis","Hemorrhage","Humans","Kidney Diseases","Risk Factors","Thromboembolism","Warfarin","Risk Assessment","Stroke"],"keywords":["Medicine","Atrial fibrillation","Stroke (engine)","Internal medicine","Cardiology","Heart failure","Warfarin","Diabetes mellitus","Risk factor","Cardiomyopathy","Disease","Framingham Risk Score","CHA2DS2–VASc score","Intensive care medicine","Ischemic stroke"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-18T19:01:10.658707Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}