Journal of Thrombosis and Haemostasis, 12: 593–594
DOI: 10.1111/jth.12558
COMMENTARY
It’s not about sex M. GREAVES College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, UK
To cite this article: Greaves M. It’s not about sex. J Thromb Haemost 2014; 12: 593–4. See also Takach Lapner S, Cohen N, Kearon C. Influence of sex on risk of bleeding in anticoagulated patients: a systematic review and meta-analysis. This issue, pp 595–605.
All anticoagulants increase the risk of bleeding, including fatal bleeds. Oral anticoagulants are in widespread use for long-term therapy because of their efficacy in reducing systemic thromboembolism, particularly ischemic stroke in subjects with atrial fibrillation, and in protection from recurrent venous thromboembolism (VTE) after a first, apparently unprovoked event. The identification of patients in whom the risk/benefit ratio favors long-term anticoagulant therapy is an example of a fundamental principle of clinical practice: primum non nocere, or ‘first do no harm.’ However, in the context of thromboprophylaxis, this is far from straightforward, not least because of limited capacity to predict anticoagulant-induced bleeding in the individual patient and the overlap between risk factors for bleeding and thromboembolism. In the spirit of personalized or stratified medicine, attempts have been made to use the key risk factors for thrombosis along with those for anticoagulant-induced bleeding in the development of algorithms designed to assist in clinical decision making. In relation to thrombosis, the CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack previously) score [1] and its modification CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus and stroke or transient ischaemic attack previously, vascular disease, age 65– 74 years, sex female) [2] have been adopted widely to identify those subjects with atrial fibrillation in whom anticoagulant therapy is justified. Although less well validated, algorithms for the prediction of recurrent venous
Correspondence: Michael Greaves, College of Life Sciences and Medicine, University of Aberdeen, Polwarth, Foresterhill, Aberdeen AB252ZD, UK. Tel.: +44 1224 437081; fax: +44 1224 437069. E-mail: [email protected] Received 3 March 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 7 March 2014 © 2014 International Society on Thrombosis and Haemostasis
thromboembolism have been promoted, such as the DASH (D-dimer elevated, age 75 years, prior hemorrhage, and hypertension) [6], HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly > 65 years, drugs- antiplatelet agents/alcohol) [7], and HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age > 75 years, reduced platelet count or function, hypertension, anemia, genetic factors relating to warfarin metabolism, excessive fall risk, stroke and prior bleeding) [8]. Disappointingly, performance in predicting bleeding was modest, with the HASBLED score performing somewhat better than the others. Poor performance was confirmed in a study by Burgess et al. [9]; agreement between models was poor, and the authors concluded that general clinical implementation cannot be recommended. These bleeding prediction models include a combination of risk factors of varying power. For example, all include age (in a range of > 60 to > 75 years), and almost all include renal impairment and previous bleeding episodes. Some feature hypertension, cancer, anemia, and other comorbidities. It is assumed in some prediction models that there is a difference in bleeding risk between men and women [10,11]. Any such difference would be of importance in judging the relative risks and benefits of long-term anticoagulation in the clinic as there is strong evidence of a difference between the sexes in risk of thrombosis―women with atrial fibrillation are more susceptible to stroke than are men with the arrhythmia, whereas recurrence of VTE after cessation
594 M. Greaves
of anticoagulant treatment given for an unprovoked episode is more likely in men than in women. This issue of a sex difference in the risk of bleeding in anticoagulated patients has been addressed through a meta-analysis of randomized controlled trials and prospective cohort studies in the current issue of the journal [12]. A well-conducted analysis indicated that in those with atrial fibrillation, by far the most frequent indication for longterm oral anticoagulant treatment, there is no difference in the risk of major bleeding between the sexes. In relation to thromboprophylaxis after VTE, the data were less robust, but the authors conclude that it is unlikely that there is a difference in major bleeding between the sexes for this indication, too. The demonstration that the patient’s sex should not be a consideration when reaching decisions regarding anticoagulant management is of some value in the clinic setting. It remains the case, however, that prediction of bleeding is challenging and inexact, perhaps with a tendency to overestimate the risk and eschew anticoagulant therapy that is justified based on the risk of thrombosis, especially in atrial fibrillation [13]. Bleeding prediction models may be of some modest assistance, but risk-benefit assessment remains a clinical art based on careful consideration of clinical risk factors of proven relevance and the informed wishes of the patient. Disclosure of Conflict of Interest The author states that he has no conflicts of interest. References 1 Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: 2864–70.
2 Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest 2010; 137: 263–72. 3 Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Douketis J. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012; 10: 1019–25. 4 Thomas IS, Sorrentino MJ. Bleeding risk prediction models in atrial fibrillation. Curr Cardiol Rep 2014; 16: 432–9. 5 Lip GYH, Banerjee A, Lagrenade I, Lane DA, Taillandier S, Fauchier L. Assessing the risk of bleeding in patients with atrial fibrillation. Circ Arryhthm Electrophysiol 2012; 5: 941–8. 6 Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, Singer DE. A new risk scheme to predict warfarinassociated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol 2011; 58: 395–401. 7 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138: 1093–100. 8 Gage BF, Yan Y, Milligan P, Waterman AD, Culverhouse R, Rich MW, Radford MJ. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006; 151: 713–9. 9 Burgess S, Crown N, Louzada ML, Dresser G, Kim RB, LazoLagner A. Clinical performance of bleeding risk scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin. J Thromb Haemost 2013; 11: 1647–54. 10 Kuijer PMM, Hutten BA, Prins MH, Buller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159: 457–60. 11 Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest 2006; 130: 1390–6. 12 Takach Lapner S, Cohen N, Kearon C. Influence of sex on risk of bleeding in anticoagulated patients: a systematic review and meta-analysis. J Thromb Haemost 2014; 12: 595–605. 13 Stafford RS, Singer DE. Recent national patterns of warfarin use in atrial fibrillation. Circulation 1998; 97: 1231–3.
© 2014 International Society on Thrombosis and Haemostasis
DOI: 10.1111/jth.12558
COMMENTARY
It’s not about sex M. GREAVES College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, UK
To cite this article: Greaves M. It’s not about sex. J Thromb Haemost 2014; 12: 593–4. See also Takach Lapner S, Cohen N, Kearon C. Influence of sex on risk of bleeding in anticoagulated patients: a systematic review and meta-analysis. This issue, pp 595–605.
All anticoagulants increase the risk of bleeding, including fatal bleeds. Oral anticoagulants are in widespread use for long-term therapy because of their efficacy in reducing systemic thromboembolism, particularly ischemic stroke in subjects with atrial fibrillation, and in protection from recurrent venous thromboembolism (VTE) after a first, apparently unprovoked event. The identification of patients in whom the risk/benefit ratio favors long-term anticoagulant therapy is an example of a fundamental principle of clinical practice: primum non nocere, or ‘first do no harm.’ However, in the context of thromboprophylaxis, this is far from straightforward, not least because of limited capacity to predict anticoagulant-induced bleeding in the individual patient and the overlap between risk factors for bleeding and thromboembolism. In the spirit of personalized or stratified medicine, attempts have been made to use the key risk factors for thrombosis along with those for anticoagulant-induced bleeding in the development of algorithms designed to assist in clinical decision making. In relation to thrombosis, the CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack previously) score [1] and its modification CHA2DS2-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus and stroke or transient ischaemic attack previously, vascular disease, age 65– 74 years, sex female) [2] have been adopted widely to identify those subjects with atrial fibrillation in whom anticoagulant therapy is justified. Although less well validated, algorithms for the prediction of recurrent venous
Correspondence: Michael Greaves, College of Life Sciences and Medicine, University of Aberdeen, Polwarth, Foresterhill, Aberdeen AB252ZD, UK. Tel.: +44 1224 437081; fax: +44 1224 437069. E-mail: [email protected] Received 3 March 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 7 March 2014 © 2014 International Society on Thrombosis and Haemostasis
thromboembolism have been promoted, such as the DASH (D-dimer elevated, age 75 years, prior hemorrhage, and hypertension) [6], HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly > 65 years, drugs- antiplatelet agents/alcohol) [7], and HEMORR2HAGES (hepatic or renal disease, ethanol abuse, malignancy, older age > 75 years, reduced platelet count or function, hypertension, anemia, genetic factors relating to warfarin metabolism, excessive fall risk, stroke and prior bleeding) [8]. Disappointingly, performance in predicting bleeding was modest, with the HASBLED score performing somewhat better than the others. Poor performance was confirmed in a study by Burgess et al. [9]; agreement between models was poor, and the authors concluded that general clinical implementation cannot be recommended. These bleeding prediction models include a combination of risk factors of varying power. For example, all include age (in a range of > 60 to > 75 years), and almost all include renal impairment and previous bleeding episodes. Some feature hypertension, cancer, anemia, and other comorbidities. It is assumed in some prediction models that there is a difference in bleeding risk between men and women [10,11]. Any such difference would be of importance in judging the relative risks and benefits of long-term anticoagulation in the clinic as there is strong evidence of a difference between the sexes in risk of thrombosis―women with atrial fibrillation are more susceptible to stroke than are men with the arrhythmia, whereas recurrence of VTE after cessation
594 M. Greaves
of anticoagulant treatment given for an unprovoked episode is more likely in men than in women. This issue of a sex difference in the risk of bleeding in anticoagulated patients has been addressed through a meta-analysis of randomized controlled trials and prospective cohort studies in the current issue of the journal [12]. A well-conducted analysis indicated that in those with atrial fibrillation, by far the most frequent indication for longterm oral anticoagulant treatment, there is no difference in the risk of major bleeding between the sexes. In relation to thromboprophylaxis after VTE, the data were less robust, but the authors conclude that it is unlikely that there is a difference in major bleeding between the sexes for this indication, too. The demonstration that the patient’s sex should not be a consideration when reaching decisions regarding anticoagulant management is of some value in the clinic setting. It remains the case, however, that prediction of bleeding is challenging and inexact, perhaps with a tendency to overestimate the risk and eschew anticoagulant therapy that is justified based on the risk of thrombosis, especially in atrial fibrillation [13]. Bleeding prediction models may be of some modest assistance, but risk-benefit assessment remains a clinical art based on careful consideration of clinical risk factors of proven relevance and the informed wishes of the patient. Disclosure of Conflict of Interest The author states that he has no conflicts of interest. References 1 Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: 2864–70.
2 Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on Atrial Fibrillation. Chest 2010; 137: 263–72. 3 Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Douketis J. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012; 10: 1019–25. 4 Thomas IS, Sorrentino MJ. Bleeding risk prediction models in atrial fibrillation. Curr Cardiol Rep 2014; 16: 432–9. 5 Lip GYH, Banerjee A, Lagrenade I, Lane DA, Taillandier S, Fauchier L. Assessing the risk of bleeding in patients with atrial fibrillation. Circ Arryhthm Electrophysiol 2012; 5: 941–8. 6 Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, Singer DE. A new risk scheme to predict warfarinassociated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol 2011; 58: 395–401. 7 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138: 1093–100. 8 Gage BF, Yan Y, Milligan P, Waterman AD, Culverhouse R, Rich MW, Radford MJ. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006; 151: 713–9. 9 Burgess S, Crown N, Louzada ML, Dresser G, Kim RB, LazoLagner A. Clinical performance of bleeding risk scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin. J Thromb Haemost 2013; 11: 1647–54. 10 Kuijer PMM, Hutten BA, Prins MH, Buller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159: 457–60. 11 Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest 2006; 130: 1390–6. 12 Takach Lapner S, Cohen N, Kearon C. Influence of sex on risk of bleeding in anticoagulated patients: a systematic review and meta-analysis. J Thromb Haemost 2014; 12: 595–605. 13 Stafford RS, Singer DE. Recent national patterns of warfarin use in atrial fibrillation. Circulation 1998; 97: 1231–3.
© 2014 International Society on Thrombosis and Haemostasis
