- Email: [email protected]
The ABC risk score for patients with atrial fibrillation
Correspondence
The study by Ziad Hijazi and colleagues (June 4, p 2302)1 provides a comprehensive validation of the age, biomarkers, and clinical history (ABC)-bleeding score, using age, three biomarkers (haemoglobin, cardiac troponin T, and GDF-15), and clinical history of bleeding to predict major bleeding events in anticoagulated patients with atrial fibrillation. Although the clinical usefulness of this approach to tailor stroke and bleeding risk in individual patients awaits further validation in real-world cohorts, the study by Hijazi and colleagues1 is a great leap forward in precision medicine and risk stratification in atrial fibrillation. However, I emphasise another important element missing in this precision medicine approach:2 the role of so-called silent cerebrovascular MRI biomarkers for stroke prevention in atrial fibrillation.3,4 As previously highlighted,4 intracranial haemorrhage is perhaps the most feared and devastating complication of anticoagulant use (even in the setting of non-vitamin K antagonists) in an ageing population with atrial fibrillation and is a major reason to stop anticoagulation, driving their underuse. Mounting evidence suggests that small-vessel disease in the brain is a key risk factor for anticoagulationrelated intracerebral haemorrhage.4 Hence, brain MRI biomarkers of small-vessel-disease tissue injury might provide additional unique features for personalised ischaemic versus haemorrhagic stroke risk assessment.3,4 For example, cerebral microbleeds detected by MRI— reflecting small extravasated blood deposits from nearby small vessels prone to haemorrhage—hold great promise as a candidate biomarker of future stroke risk.4,5 Their detection in www.thelancet.com Vol 388 October 22, 2016
an ever-increasing number of patients with stroke and cognitive complaints, and in healthy elderly individuals with atrial fibrillation, creates thorny clinical dilemmas in regard to the safety of the administration of anti-thrombotics.5 Uncertainty remains, and the American Heart Association and American Stroke Association are developing a scientific guidance statement on the topic. Additionally, a newly formed initiative for collaborative meta-analyses in cerebral microbleeds (META-MICROBLEEDS), 6 including their relevance in anticoagulation decisions, is underway. Whether the biomarker approach suggested by Hijazi and colleagues 1 can be augmented by MRI biomarkers of not-so-silent cerebrovascular disease should be explored as part of a more tailored precision medicine strategy.3 I declare no competing interests.
Andreas Charidimou [email protected] J Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA 1
2
3
4
5
6
Hijazi Z, Oldgren J, Lindbäck J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387: 2302–11. Kirchhof P, Fabritz L. Can biomarkers balance stroke and bleeding risk? Lancet 2016; 387: 2266–68. Fisher M. MRI screening for chronic anticoagulation in atrial fibrillation. Front Neurol 2013; 4: 137. Charidimou A, Shakeshaft C, Werring DJ. Cerebral microbleeds on magnetic resonance imaging and anticoagulant-associated intracerebral hemorrhage risk. Front Neurol 2012; 3: 133. Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and recurrent stroke risk: systematic review and meta-analysis of prospective ischemic stroke and transient ischemic attack cohorts. Stroke 2013; 44: 995–1001. Charidimou A, Soo Y, Heo JH, Srikanth V, META-MICROBLEEDS Consortium. A call for researchers to join the META-MICROBLEEDS Consortium. Lancet Neurol 2016; 15: 900.
Ziad Hijazi and colleagues’ 1 age, biomarkers, and clinical history (ABC) score yields promise as a new standard for assessment of bleeding risk in patients with atrial fibrillation
and supports the role of biomarkers in the field of arrhythmic disorders. Unfortunately, it also highlights the overlap of some variables (GDF-15, cardiac troponin T, and age), which are not only associated with bleeding, but are also known risk factors for stroke and systemic embolism.2,3 New thromboembolic risk stratification schemes such as ATRIA,4 R2CHADS2,5 and ABC-stroke6 have been proposed, but the time has come for a new notion of integrated risk stratification for patients with atrial fibrillation. To use two separate risk classifications to assess the two ends of a continuous spectrum (thrombosis vs bleeding) seems artificial and provides unclear guidance in the frequent setting of increased bleeding and thrombotic risk. We propose that a combined risk score assessing thromboembolic risk and simultaneously adjusting or balancing for bleeding risk, providing a net risk or benefit estimation, might be the way to achieve a personalised treatment in this population. This proposal could potentially allow tailoring of anticoagulation according to each patient’s net risk, possibly allowing high-intensity anticoagulation regimens for patients with high thromboembolic risk but low bleeding risk and low-intensity anticoagulation regimens in those with low-tomoderate thromboembolic risk and high bleeding tendency. To integrate and merge the different risk assessment tools (bleeding and thromboembolic risk scores) might be the way forward, including variables signalling only high thromboembolic risk or adjusting for thrombotic risk factors for the bleeding tendency. In the future, structural information when it is validated (eg, left atrial appendage morphology or velocities) could also be incorporated to refine the scoring system. We declare no competing interests.
*Rui Providencia, Pier D Lambiase [email protected]
Nataliia K
The ABC risk score for patients with atrial fibrillation
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1979
Correspondence
Barts Heart Centre, Barts Health NHS Trust, London EC1A 7BE, UK (RP, PDL); and Institute of Cardiovascular Science, University College London, London, UK (PDL) 1
2
3
4
5
6
Hijazi Z, Oldgren J, Lindbäck J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387: 2302–11. Wallentin L, Hijazi Z, Andersson U, et al. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014; 130: 1847–58. Hijazi Z, Wallentin L, Siegbahn A, et al. High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. J Am Coll Cardiol 2014; 63: 52–61. van den Ham HA, Klungel OH, Singer DE, Leufkens HG, van Staa TP. Comparative performance of ATRIA, CHADS2, and CHA2DS2-VASc risk scores predicting stroke in patients with atrial fibrillation: results from a national primary care database. J Am Coll Cardiol 2015; 66: 1851–59. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation 2013; 127: 224–32. Hijazi Z, Lindbäck J, Alexander JH, et al. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation. Eur Heart J 2016; 37: 1582–90.
Authors’ reply
For the digital calculator see http://www.ucr.uu.se/en/services
1980
We thank the correspondents for their comments on our Article 1 concerning the new biomarker-based age, biomarkers, and clinical history (ABC)-bleeding risk score in patients with atrial fibrillation. The biomarker field has matured greatly in recent years and acquired increased notice also in clinical cardiology guidelines.2 Apart from the robust methods by which the ABC-bleeding risk score was developed and validated, another key advantage of the score is easy adaptability, in terms of use and future refinement. The strongest clinical variables, age and history of bleeding, were identified. By addition of the most prognostic clinically
available biomarkers, haemoglobin, cardiac troponin T, and GDF-15 or renal function, the ABC-bleeding score was constructed. GDF-15 and haemoglobin seem to be specific markers of bleeding risk.1,3 The field of biomarker research in atrial fibrillation is, however, growing considerably and even better and more specific novel biomarkers could subsequently be identified and validated, which in the future might alter the composition of the biomarkers in the ABC-bleeding score. This growth would be a welcomed evolution in our and others’ continuous efforts to improve risk stratification in atrial fibrillation. Introduction of non-vitamin K antagonist oral anticoagulants with better safety and efficacy profile as compared with warfarin has also substantially influenced risk assessment and management of patients with atrial fibrillation.4 Because the ABC-bleeding risk score is continuous, new treatment decision strategies might easily be implemented, which makes the ABC score uniquely dynamic and conceptually future proof. Rui Providencia and Pier Lambiase suggest an integrated risk score. We believe this stepwise and separate approach for development and validation of stroke and bleeding risk models to be advantageous.1,5 Insights into each risk separately are valuable for both patient information and informed decisions. This approach still permits, and coincides with our intention of, simultaneous use of both the ABC-stroke and ABC-bleeding risk scores. Because available treatment alternatives for stroke prevention in atrial fibrillation have different profiles for risk of ischaemic stroke and bleeding, combined use of the ABC-bleeding and ABC-stroke scores provides useful decision support for personalisation of treatment strategies. This decision support is illustrated by the digital calculator at the Uppsala Clinical Research Center. The GDF-15 assay by Roche,
Mannheim, Germany, is commercially available, and the ABC-bleeding score might therefore be fully implemented. At this time, we are planning an assessment of implementation of these new biomarker-based ABC decision support tools for improved risk assessment in routine health care. ZH and JL have received lecture fees and institutional research grants from Boehringer Ingelheim, and consulting fees and institutional research grants from Bristol-Myers Squibb/Pfizer, during the conduct of the study. JO has received institutional research grants and consulting and lecture fees from Boehringer Ingelheim, Bayer, and Bristol-Myers Squibb/Pfizer. AS has received institutional research grants from Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and GlaxoSmithKline, during the conduct of the study; and institutional research grants from AstraZeneca, outside the submitted work. LW has received an institutional research grant, consulting fee, lecture fee, and travel support from Bristol-Myers Squibb/Pfizer and Boehringer Ingelheim; institutional research grants from Roche; an institutional research grant, consulting fee, lecture fee, travel support, and honoraria from GlaxoSmithKline, during the conduct of the study; institutional research grants from Merck & Co; consulting fees from Abbott; an institutional research grant, consulting fee, lecture fee, and travel support from AstraZeneca, outside the submitted work; and holds two patents involving GDF-15.
*Ziad Hijazi, Jonas Oldgren, Johan Lindbäck, Agneta Siegbahn, Lars Wallentin [email protected] Department of Medical Sciences, Cardiology, Uppsala University, S-751 85 Uppsala, Sweden (ZH, JO, LW); and Department of Medical Sciences, Clinical Chemistry, Uppsala University (AS), and Uppsala Clinical Research Center (ZH, JO, JL, AS, LW), Uppsala University, Uppsala, Sweden 1
2
3
Hijazi Z, Oldgren J, Lindbäck J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387: 2302–11. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Endorsed by the European Stroke Organisation (ESO). Eur Heart J 2016; published online Aug 27. DOI:http://dx.doi.org/10.1093/eurheartj/ ehw210. Wallentin L, Hijazi Z, Andersson U, et al. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014; 130: 1847–58.
www.thelancet.com Vol 388 October 22, 2016
The study by Ziad Hijazi and colleagues (June 4, p 2302)1 provides a comprehensive validation of the age, biomarkers, and clinical history (ABC)-bleeding score, using age, three biomarkers (haemoglobin, cardiac troponin T, and GDF-15), and clinical history of bleeding to predict major bleeding events in anticoagulated patients with atrial fibrillation. Although the clinical usefulness of this approach to tailor stroke and bleeding risk in individual patients awaits further validation in real-world cohorts, the study by Hijazi and colleagues1 is a great leap forward in precision medicine and risk stratification in atrial fibrillation. However, I emphasise another important element missing in this precision medicine approach:2 the role of so-called silent cerebrovascular MRI biomarkers for stroke prevention in atrial fibrillation.3,4 As previously highlighted,4 intracranial haemorrhage is perhaps the most feared and devastating complication of anticoagulant use (even in the setting of non-vitamin K antagonists) in an ageing population with atrial fibrillation and is a major reason to stop anticoagulation, driving their underuse. Mounting evidence suggests that small-vessel disease in the brain is a key risk factor for anticoagulationrelated intracerebral haemorrhage.4 Hence, brain MRI biomarkers of small-vessel-disease tissue injury might provide additional unique features for personalised ischaemic versus haemorrhagic stroke risk assessment.3,4 For example, cerebral microbleeds detected by MRI— reflecting small extravasated blood deposits from nearby small vessels prone to haemorrhage—hold great promise as a candidate biomarker of future stroke risk.4,5 Their detection in www.thelancet.com Vol 388 October 22, 2016
an ever-increasing number of patients with stroke and cognitive complaints, and in healthy elderly individuals with atrial fibrillation, creates thorny clinical dilemmas in regard to the safety of the administration of anti-thrombotics.5 Uncertainty remains, and the American Heart Association and American Stroke Association are developing a scientific guidance statement on the topic. Additionally, a newly formed initiative for collaborative meta-analyses in cerebral microbleeds (META-MICROBLEEDS), 6 including their relevance in anticoagulation decisions, is underway. Whether the biomarker approach suggested by Hijazi and colleagues 1 can be augmented by MRI biomarkers of not-so-silent cerebrovascular disease should be explored as part of a more tailored precision medicine strategy.3 I declare no competing interests.
Andreas Charidimou [email protected] J Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA 1
2
3
4
5
6
Hijazi Z, Oldgren J, Lindbäck J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387: 2302–11. Kirchhof P, Fabritz L. Can biomarkers balance stroke and bleeding risk? Lancet 2016; 387: 2266–68. Fisher M. MRI screening for chronic anticoagulation in atrial fibrillation. Front Neurol 2013; 4: 137. Charidimou A, Shakeshaft C, Werring DJ. Cerebral microbleeds on magnetic resonance imaging and anticoagulant-associated intracerebral hemorrhage risk. Front Neurol 2012; 3: 133. Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and recurrent stroke risk: systematic review and meta-analysis of prospective ischemic stroke and transient ischemic attack cohorts. Stroke 2013; 44: 995–1001. Charidimou A, Soo Y, Heo JH, Srikanth V, META-MICROBLEEDS Consortium. A call for researchers to join the META-MICROBLEEDS Consortium. Lancet Neurol 2016; 15: 900.
Ziad Hijazi and colleagues’ 1 age, biomarkers, and clinical history (ABC) score yields promise as a new standard for assessment of bleeding risk in patients with atrial fibrillation
and supports the role of biomarkers in the field of arrhythmic disorders. Unfortunately, it also highlights the overlap of some variables (GDF-15, cardiac troponin T, and age), which are not only associated with bleeding, but are also known risk factors for stroke and systemic embolism.2,3 New thromboembolic risk stratification schemes such as ATRIA,4 R2CHADS2,5 and ABC-stroke6 have been proposed, but the time has come for a new notion of integrated risk stratification for patients with atrial fibrillation. To use two separate risk classifications to assess the two ends of a continuous spectrum (thrombosis vs bleeding) seems artificial and provides unclear guidance in the frequent setting of increased bleeding and thrombotic risk. We propose that a combined risk score assessing thromboembolic risk and simultaneously adjusting or balancing for bleeding risk, providing a net risk or benefit estimation, might be the way to achieve a personalised treatment in this population. This proposal could potentially allow tailoring of anticoagulation according to each patient’s net risk, possibly allowing high-intensity anticoagulation regimens for patients with high thromboembolic risk but low bleeding risk and low-intensity anticoagulation regimens in those with low-tomoderate thromboembolic risk and high bleeding tendency. To integrate and merge the different risk assessment tools (bleeding and thromboembolic risk scores) might be the way forward, including variables signalling only high thromboembolic risk or adjusting for thrombotic risk factors for the bleeding tendency. In the future, structural information when it is validated (eg, left atrial appendage morphology or velocities) could also be incorporated to refine the scoring system. We declare no competing interests.
*Rui Providencia, Pier D Lambiase [email protected]
Nataliia K
The ABC risk score for patients with atrial fibrillation
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1979
Correspondence
Barts Heart Centre, Barts Health NHS Trust, London EC1A 7BE, UK (RP, PDL); and Institute of Cardiovascular Science, University College London, London, UK (PDL) 1
2
3
4
5
6
Hijazi Z, Oldgren J, Lindbäck J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387: 2302–11. Wallentin L, Hijazi Z, Andersson U, et al. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014; 130: 1847–58. Hijazi Z, Wallentin L, Siegbahn A, et al. High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin. J Am Coll Cardiol 2014; 63: 52–61. van den Ham HA, Klungel OH, Singer DE, Leufkens HG, van Staa TP. Comparative performance of ATRIA, CHADS2, and CHA2DS2-VASc risk scores predicting stroke in patients with atrial fibrillation: results from a national primary care database. J Am Coll Cardiol 2015; 66: 1851–59. Piccini JP, Stevens SR, Chang Y, et al. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation 2013; 127: 224–32. Hijazi Z, Lindbäck J, Alexander JH, et al. The ABC (age, biomarkers, clinical history) stroke risk score: a biomarker-based risk score for predicting stroke in atrial fibrillation. Eur Heart J 2016; 37: 1582–90.
Authors’ reply
For the digital calculator see http://www.ucr.uu.se/en/services
1980
We thank the correspondents for their comments on our Article 1 concerning the new biomarker-based age, biomarkers, and clinical history (ABC)-bleeding risk score in patients with atrial fibrillation. The biomarker field has matured greatly in recent years and acquired increased notice also in clinical cardiology guidelines.2 Apart from the robust methods by which the ABC-bleeding risk score was developed and validated, another key advantage of the score is easy adaptability, in terms of use and future refinement. The strongest clinical variables, age and history of bleeding, were identified. By addition of the most prognostic clinically
available biomarkers, haemoglobin, cardiac troponin T, and GDF-15 or renal function, the ABC-bleeding score was constructed. GDF-15 and haemoglobin seem to be specific markers of bleeding risk.1,3 The field of biomarker research in atrial fibrillation is, however, growing considerably and even better and more specific novel biomarkers could subsequently be identified and validated, which in the future might alter the composition of the biomarkers in the ABC-bleeding score. This growth would be a welcomed evolution in our and others’ continuous efforts to improve risk stratification in atrial fibrillation. Introduction of non-vitamin K antagonist oral anticoagulants with better safety and efficacy profile as compared with warfarin has also substantially influenced risk assessment and management of patients with atrial fibrillation.4 Because the ABC-bleeding risk score is continuous, new treatment decision strategies might easily be implemented, which makes the ABC score uniquely dynamic and conceptually future proof. Rui Providencia and Pier Lambiase suggest an integrated risk score. We believe this stepwise and separate approach for development and validation of stroke and bleeding risk models to be advantageous.1,5 Insights into each risk separately are valuable for both patient information and informed decisions. This approach still permits, and coincides with our intention of, simultaneous use of both the ABC-stroke and ABC-bleeding risk scores. Because available treatment alternatives for stroke prevention in atrial fibrillation have different profiles for risk of ischaemic stroke and bleeding, combined use of the ABC-bleeding and ABC-stroke scores provides useful decision support for personalisation of treatment strategies. This decision support is illustrated by the digital calculator at the Uppsala Clinical Research Center. The GDF-15 assay by Roche,
Mannheim, Germany, is commercially available, and the ABC-bleeding score might therefore be fully implemented. At this time, we are planning an assessment of implementation of these new biomarker-based ABC decision support tools for improved risk assessment in routine health care. ZH and JL have received lecture fees and institutional research grants from Boehringer Ingelheim, and consulting fees and institutional research grants from Bristol-Myers Squibb/Pfizer, during the conduct of the study. JO has received institutional research grants and consulting and lecture fees from Boehringer Ingelheim, Bayer, and Bristol-Myers Squibb/Pfizer. AS has received institutional research grants from Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, and GlaxoSmithKline, during the conduct of the study; and institutional research grants from AstraZeneca, outside the submitted work. LW has received an institutional research grant, consulting fee, lecture fee, and travel support from Bristol-Myers Squibb/Pfizer and Boehringer Ingelheim; institutional research grants from Roche; an institutional research grant, consulting fee, lecture fee, travel support, and honoraria from GlaxoSmithKline, during the conduct of the study; institutional research grants from Merck & Co; consulting fees from Abbott; an institutional research grant, consulting fee, lecture fee, and travel support from AstraZeneca, outside the submitted work; and holds two patents involving GDF-15.
*Ziad Hijazi, Jonas Oldgren, Johan Lindbäck, Agneta Siegbahn, Lars Wallentin [email protected] Department of Medical Sciences, Cardiology, Uppsala University, S-751 85 Uppsala, Sweden (ZH, JO, LW); and Department of Medical Sciences, Clinical Chemistry, Uppsala University (AS), and Uppsala Clinical Research Center (ZH, JO, JL, AS, LW), Uppsala University, Uppsala, Sweden 1
2
3
Hijazi Z, Oldgren J, Lindbäck J, et al. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387: 2302–11. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Endorsed by the European Stroke Organisation (ESO). Eur Heart J 2016; published online Aug 27. DOI:http://dx.doi.org/10.1093/eurheartj/ ehw210. Wallentin L, Hijazi Z, Andersson U, et al. Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation 2014; 130: 1847–58.
www.thelancet.com Vol 388 October 22, 2016