Mengxin Zhou, Rui Sun, Yuexin Chen＊

Department of Vascular Surgery, Peking Union Medical College Hospital,Chinese Medical Sciences Academy & Peking Union Medical College,Beijing 100730, China

Key words: venous thromboembolism; coronary heart disease; antithrombotic therapy;combination therapy

Abstract Patients with venous thromboembolism (VTE) and concurrent coronary heart disease (CHD) are not rare in clinic. The main challenge in the treatment for these patients is that the antithrombotic therapies for VTE and CHD are different from each other, but the combination of the two therapeutic strategies would increase the risk of bleeding. There is a need to optimize the antithrombotic therapeutic scheme on the basis of individual conditional, in order to balance the therapeutic effects and the bleeding risk. This article discussed the appropriate antithrombotic therapy when balancing the effectiveness and the risk in different circumstance of concurrence of VTE and CHD, such as combining anticoagulation therapy, dual antiplatelet therapy (DAPT),triple antithrombotic therapy (TAT), thrombolytic therapy and extending therapy, in order to provide safe,standard and effective therapeutic schemes for the clinical management of these patients. In the meantime, this article also provides perspectives regarding the application of novel non-vitamin K anticoagulants (NOACs) and the assessment tools of bleeding risk.

BOTH venous thromboembolism (VTE) and coronary heart disease (CHD) are common conditions in the modern medicine. The deep venous thrombosis (DVT) and pulmonary embolism (PE), the main clinical types of VTE, occur in 17.1 and 3.9 per 100 000 respectively annually in China,1and these numbers may be higher in Europe and America.2,3CHD, including chronic coronary artery disease (CAD) and acute coronary syndrome (ACS),has been the leading cause of death in developed countries,4and China is not an exception. In 2014,the Chinese rural mortality of heart disease is 143.72 per 100 000, while the urban mortality is 261.99 per 100 000.5Nevertheless, the accurate prevalence data of patients of VTE with concurrent CHD are still lacking, though some studies6,7have indicated that these patients are not unusual in clinic.

However, VTE and CHD have been considered separately as two entities for a long time, mainly because of their different anatomy and mechanism of thrombosis. Arterial thrombosis, the main cause of CHD, is largely a matter of activation of platelet,whereas venous thrombosis is mainly an activation of clotting system. Correspondingly，the basic therapy for arterial thrombosis is using antiplatelet drugs, while for venous thrombosis, it would be essential to choose a proper anticoagulants among a variety of anticoagulants. Neither antiplatelet nor anticoagulant therapy alone is effective enough to cure the patients with VTE and concurrent CHD completely; however, combining antiplatelet therapy with anticoagulants would absolutely raise the risk of hemorrhage.

Recently, some studies suggested that the mechanisms of the two diseases may not as different as we had thought. They possibly share common risk factors,8-11and even there may be a causal relationship, or they might be the risk factor to each other.12-14These considerations lay the foundation of optimizing the strategy of the conjunctive therapy.

Combination therapies for VTE Concurrent with stable CHD

According to the Chinese guideline published in 2016,15for the patients of PE concurrent with stable CHD (stable angina pectoris, ischemic cardiomyopathy, or latent coronary heart disease), the anticoagulation treatment is the combination of parenteral and oral anticoagulation (OAC)， which is the same as for PE alone. This is in agreement with some Chinese experts,16though there are no evidence-based data to support or contradict it. A specific usage in line with European Society of Cardiology (ESC) guidelines17is that using parenteral anticoagulation immediately while waiting for the results of diagnostic tests that are to confirm the risk of PE and to decide whether thrombolytic therapy is necessary, meanwhile initiating oral anticoagulation therapy as soon as possible, best on the same day.

But so far, there hasn’t been a unanimous standard for the combination of parenteral and oral anticoagulation as an appropriate treatment for the discussed patients. Castellucci et al18published a careful systemic review and meta-analysis, which compared several combinations of parenteral plus oral anticoagulation therapies that were frequently used,and suggested that unfractionated heparin-vitamin K anticoagulants (UFH-VKA) combination may be the least effective, rivaroxaban or apixaban may have the lowest risk of hemorrhage, and low molecular weight heparin-vitamin K anticoagulants (LMWH-VKA) combination has no significant difference from the other combinations in terms of the safety and effectiveness.These findings made the LMWH-VKA a better choice,with rivaroxaban or apixaban as an alternative to VKA.Both rivaroxaban and apixaban are novel non-vitamin K anticoagulants (NOACs), and have been found equal or superior to VKAs not only in effectiveness but also in safety in recent years.19This has made them the first recommendation by American College of Chest Physicians (ACCP).20The advantages of NOACs, as listed in detail in an article by Verdecchia et al,21included lower risks of hemorrhagic stroke, intracranial bleeding and thromboembolism, stable international normalized ratio (INR) control, fewer interactions with drugs and food, etc. In spite of these advantages, not all NOACs are proper to replace VKAs for patients with VTE concurrent with CHD. A study has pointed out that among those promising agents, dabigatran increases the risk of myocardial infarction (MI), while apixaban decreased the risk of both arterial and venous thrombotic events.22Consequently, carefully choosing a NOAC is deserved when using parenteral plus oral anticoagulation as joint scheme.

Triple antithrombotic therapies for VTE concurrent with ACS (except for STEMI)

The most frequently recommended and used therapeutic scheme in clinics is triple antithrombotic therapy(TAT) for patients with DVT or those at low-risk of PE(defined as normal blood presure and have neither heart dysfunction nor elevated biomarkers) and concurrent acute coronary syndrome (ACS), with exception of ST-segment elevation myocardial infarction(STEMI). The TAT consists of a dual antiplatelet therapy (DAPT) and an OAC. To be specific, the TAT mostly refers to applying VKA (INR 2.0?2.5), aspirin (100 mg/d) and clopidogrel (75 mg/d), with one of NOACs as an alternative to the VKA (rivaroxaban: 15 mg twice daily for 3 weeks, followed by 20 mg once daily; or apixaban:10 mg twice daily for 7 days, followed by 5 mg twice daily; or dabigatran: 150 mg or 110 mg twice daily for people older than 80 years old) for 3 months.15,17

However, there are little data to support the utility of TAT for the discussed patients, resulting in the lack of precise recommendations in guidelines on this issue. Meanwhile, the apparent increase of major bleeding caused by TAT has also restricted its applica-tion, though replacing warfarin with an NOAC may be a bit better.23,24A review of randomized control trials by Jeremy et al25indicated that for ACS patients, rivaroxaban or apixaban plus DAPT contributed to a small reduction of ischemic events, but increased the bleeding risk obviously. This review also pointed out that if choosing TAT, it is important to monitor INR carefully and shorten the duration of medication time.

Thrombolytic therapies once PE or STEMI happens

For patients who have either STEMI or high-risk PE(defined as acute pulmonary embolism that systolic blood pressure is below 90 mmHg, or systolic pressure has dropped by at least 40 mmHg for more than 15 minutes), the first choice of treatment is prompt thrombolysis as long as there is no contraindication,which has been included in a Chinese guideline.15Particularly, when high-risk PE and STEMI happens simultaneously, thrombolytic therapy is definitely utile to restore the perfusion of both coronary artery and pulmonary artery.

However, for patients who is at intermediate-risk of PE (defined as preserved systolic blood pressure with dysfunction of right ventricle on echocardiography and/or elevated cardiac biomarkers), it is still controversial whether thrombolysis is appropriate or not.Recently, Sanchez et al26carefully analyzed several randomized trials and concluded that for intermediate-risk PE, thrombolytic therapy should be considered only when the patient is under 75 years old and at low risk of bleeding. In term of the dangerousness, a multicentric randomized controlled trial performed by Chen Wang et al27compared the validity and safety of a full-dose recombinant tissue-type plasminogen activator (rt-PA) with a half-dose rt-PA, coming to a verdict that the half-dose rt-PA had a lower bleeding risk (3% versus 10%), while their effects were parallel. The Moderate Pulmonary Embolism Treated with Thrombolysis trial28reached a similar conclusion that the “safe dose” of rt-PA was effective and safe. Yet the prognosis of intermediate-risk PE is not as poor as high-risk PE, so it is deserved to weigh the benefit of using thrombolytic therapy verse its risk of bleeding in this situation. More high-quality evidence-based data and population-based clinical trials are still needed.

In situation that a patient of STEMI has received percutaneous coronary intervention (PCI), which should not be put in the first place if there is no need of urgent stent implantation,15combination of antithrombotic therapy should be considered. A study by DeEugenio et al29which enrolled 97 patients revealed that warfarin was an independent predictor of major bleeding. Since neither OAC nor DAPT is sufficient to cure the concurrence of STEMI and VTE, none of them is recommended to be a substitute of TAT.30Thereby in the guidelines it is recommended that TAT should be used but with a shortened medication time of 2-4 weeks,15because short-term usage of TAT yield an acceptable bleeding risk. Another essay by Khurram et al31put a more concrete and rational advice, which was choosing therapeutic scheme according to the patients′risks of bleeding. For patients at low or mediate risk of bleeding, TAT is the best option; for patients at high-risk of bleeding, warfarin plus clopidogrel should be considered. Another review has also concluded that the effect of VKA plus clopidogrel were comparable with the TAT,but was superior to the other strategies.23Warfarin plus aspirin was also demonstrated as an acceptable treatment by a meta-analysis32and a piece of literature.16

Rivaroxaban is the first and the only NOAC by far that has been supported by RCTs data on patients with atrial fibrillation (AF) who have undergone PCI. It has attracted an extensive interest, because its complications has been far beyond our expectation. A recent study by Gibson et al33which involved 2124 participants who had AF and had undergone PCI is quiet impressing. The patients were divided into two groups,one group was administrated rivaroxaban (15 mg once daily) plus P2Y12inhibitor for 12 months, the other was administrated rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months. Both groups had significant lower bleeding rates than the group adopting standard therapy (VKA plus DAPT), while their efficacy rates were similar. In this study, the author also mentioned that for patients who were receiving DAPT because of ACS, a very low dose of rivaroxaban (2.5 mg twice daily) plus DAPT would reduce the death rates caused by cardiovascular diseases, MI and stroke.These outcome data were valuable for the consideration of adopting a low dose of rivaroxaban plus DAPT in the clinical management of patients who have VTE and are about to undergo PCI, since the therapy for these patients also includes anticoagulation and antiplatelet. More researches and evidence-based data are needed in this area.

Extending therapy

For patients with VTE, OAC is admitted as the tradi-tional extending therapy, primarily including one of NOACs or warfarin for at least 3 months; while for CHD patients, aspirin can be administered for a lifelong time as the extending therapy. Some Chinese scholars proposed that the extending therapy should use warfarin or other oral anticoagulants, but they also come up with that aspirin may be benefit to VTE patients.For patients who are reluctant to use warfarin or have discontinued anticoagulant therapy, they can use aspirin alternatively.15,16A literature review by Mekaj et al34emphasized that aspirin had effectiveness in prevention and treatment of both VTE and CHD. Becattini et al35performed a study involving 402 patients and concluded that using aspirin for long-term therapy decreased the recurrence rate of VTE (5.9% versus 11%), with no increase of major bleeding rate. Though in another study by Brighton et al, the decline of the recurrent VTE was not statistically significant,36both studies had affirmed the validity of employing aspirin in extending therapy.

Assessment of bleeding risk

In the process of antithrombotic therapy for patients with both VTE and CHD, it is critical to assess bleeding risks of patients individually. At present, there are several clinical prediction scales, such as the Kuijer,37RIETE,38HAS-BLED,39ATRIA,40HEMORR2HAGES41and ACCP.42However, the predictive values of these scales from limited studies were not satisfied enough and their discriminatory performances were regarded to be poor.43-45Another study also pointed out that among a variety of bleeding risk estimation tools, none has been supported by evidence-based data.46Studies suggested that HAS-BLED may be a good choice for the assessment of bleeding risk of patient with AF and is undergoing anticoagulation therapy.47-50But for patients who have had PCI and need short- or long-term DAPT,Costa et al51suggested that CRUSADE performed better than HAS-BLED in predicting major bleeding. This situation has also pointed out a direction for profound research in future.

Conclusions

In clinical management of patients with VTE and concurrent CHD, it is crucial to balance the effect and risk according to the individual situation when choosing the proper therapeutic scheme. For patients with VTE and stable CHD, LMWH-VKA may be the most available treatment, and a proper NOAC as an alternate to VKA may be more beneficial. Although NOACs are promising agents, evidence-based data are still needed to identify their indications. Whether TAT is proper for patients with VTE and ACS except for STEMI is still unknown; once TAT is applied, monitoring INR carefully and shortening therapeutic duration time are needed.Thrombolytic therapy should be used for high-risk PE patients with STEMI, while the treatment for intermediate-risk PE patients is still in dispute. For STEMI patents who have received PCI, the proper therapy should be based on their individual bleeding risk, of which the effective assessment methods are still lacking and more investigations are needed.

REFERENCES

1. Cheuk BL, Cheung GC, Cheng SW. Epidemiology of venous thromboembolism in a Chinese population. Br J Surg 2004; 91(4): 424-8. doi: 10.1002/bjs.4454.

2. Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis 2016; 41(1): 3-14. doi: 10.1007/s11239-015-1311-6.

3. Liao S, Woulfe T, Hyder S, et al. Incidence of venous thromboembolism in different ethnic groups: a regional direct comparison study. J Thromb Haemost 2014;12(2): 214-9. doi: 10.1111/jth.12464.

4. Sanchis-Gomar F, Perez-Quilis C, Leischik R, et al. Epidemiology of coronary heart disease and acute coronary syndrome. Ann Transl Med 2016; 4(13): 256.doi: 10.21037/atm.2016.06.33.

5. Sui H, Chen WW, Wang W. Interpretation of report on cardiovascular diseases in China (2015). Chin J Cardiovasc Med 2016; 21(4): 259-61. Chinese. doi:10.3969/j.issn.1007-5410.2016.04.001.

6. Fang BM. Emphasizing the diagnosis and treatment of pulmonary thromboembolism concurrent with coronary heart disease. Chin J Cardiovasc Med 2008; 18(3): 167-70. Chinese. doi: 10.3969/j.issn.1007-5410.2008.03.003.

7. Zhang XF, Zhu GF, Liu S. Clinical characteristics and intervention of pulmonary thromboembolism patients with coronary atherosclerotic heart disease. Chin General Practice 2011; 14(31): 3577-9. Chinese. doi:10.3969/j.issn.1007-9572.2011.31.013.

8. Braekkan SK, Mathiesen EB, Nj?lstad I, et al. Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Troms? study. J Thromb Haemost 2008; 6(11): 1851-7. doi:10.1111/j.1538-7836.2008.03102.x.

9. Bruzelius M, Strawbridge RJ, Trégou?t DA, et al. Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism. Thromb Res 2014; 134(2): 426-32. doi: 10.1016/j.thromres.2014.03.054.

10. Franchini M, Mannucci PM. Venous and arterial thrombosis: different sides of the same coin? Eur J Intern Med 2008; 19(7): 476-81. doi: 10.1016/j.ejim.2007.10.019.

11. Mi Y, Yan S, Lu Y, et al. Venous thromboembolism has the same risk factors as atherosclerosis: A Prisma compliant systemic review and meta-analysis. Medicine (Baltimore) 2016; 95(32): e4495. doi: 10.1097/MD.0000000000004495.

12. Lijfering WM, Flinterman LE, Vandenbroucke JP, et al.Relationship between venous and arterial thrombosis:a review of the literature from a causal perspective.Semin Thromb Hemost 2011; 37(8): 885-96. doi:10.1055/s-0031-1297367.

13. S?rensen HT, Horvath-Puho E, S?gaard KK, et al. Arterial cardiovascular events, statins, low-dose aspirin and subsequent risk of venous thromboembolism:a population-based case-control study. J Thromb Haemost 2009; 7(4): 521-8. doi: 10.1111/j.1538-7836.2009.03279.x.

14. S?rensen HT, Horvath-Puho E, Pedersen L, et al. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 2007; 370(9601): 1773-9.doi: 10.1016/S0140-6736(07)61745-0.

15. Committee of Experts on Rational Drug Use of the National Health and Family Planning Commission of the PRC, Chinese Pharmacists Association. Guideline of rational drug therapy for the Coronary heart disease.Chin J Fronti Med Sci 2016(06): 19-108. Chinese. doi:10.3969/j.issn.1674-7372.2016.06.007.

16. Xiong CM, Hu EC. Strategy of diagnosis and treatment in the coronary heart disease that concurrent with pulmonary thromboembolism. Chin J Clinicians 2013; 7(15): 6788-91. Chinese. doi: 10.3969/cma.j.issn.1674-0785.2013.15.002.

17. Konstantinides SV, Torbicki A, Agnelli G, et al. Task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35(43): 3033-69, 3069a-3069k. doi:10.1093/eurheartj/ehu283.

18. Castellucci LA, Cameron C, Le Gal G, et al. Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA 2014; 312(11): 1122-35.doi: 10.1001/jama.2014.10538.

19. van der Hulle T, Kooiman J, den Exter PL, et al. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12(3): 320-8. doi: 10.1111/jth.12485.

20. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest 2012; 141(2 Suppl): e44S-e88S. doi: 10.1378/chest.11-2292.

21. Verdecchia P, Angeli F, Aita A, et al. Why switch from warfarin to NOACs? Intern Emerg Med 2016; 11(3):289-93. doi: 10.1007/s11739-016-1411-0.

22. Prandoni P, Milan M, Barbar S, et al. Incidence of arterial embolism in patients on treatment with old and new anticoagulants for venous thromboembolism.Semin Thromb Hemost 2015; 41(2): 154-9. doi:10.1055/s-0035-1544162.

23. Rohla M, Weiss TW, Wojta J, et al. Double or triple antithrombotic combination therapy in patients who need anticoagulation and antiplatelet therapy in parallel. Eur Heart J Cardiovasc Pharmacother 2015; 1(3):191-7. doi: 10.1093/ehjcvp/pvv014.

24. Asencio LA, Huang JJ, Alpert JS. Combining antiplatelet and antithrombotic therapy (triple therapy): what are the risks and benefits? Am J Med 2014; 127(7):579-85. doi: 10.1016/j.amjmed.2014.02.030.

25. Paikin JS, Wright DS, Eikelboom JW. Effectiveness and safety of combined antiplatelet and anticoagulant therapy: a critical review of the evidence from randomized controlled trials. Blood Rev 2011; 25(3):123-9. doi: 10.1016/j.blre.2011.01.007.

26. Sanchez O, Planquette B, Meyer G. Management of massive and submassive pulmonary embolism: focus on recent randomized trials. Curr Opin Pulm Med 2014; 20(5): 393-9. doi: 10.1097/MCP.0000000000000089.

27. Wang C, Zhai Z, Yang Y, et al. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest 2010; 137(2): 254-62. doi: 10.1378/chest.09-0765.

28. Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol 2013; 111(2): 273-7. doi:10.1016/j.amjcard.2012.09.027.

29. DeEugenio D, Kolman L, DeCaro M, et al. Risk of major bleeding with concomitant dual antiplatelet therapy after percutaneous coronary intervention in patients receiving long-term warfarin therapy. Pharmacotherapy 2007; 27(5): 691-6. doi: 10.1592/phco.27.5.691.

30. Saheb KJ, Deng BQ, Hu QS, et al. Triple antithrombotic therapy versus double antiplatelet therapy after percutaneous coronary intervention with stent implantation in patients requiring chronic oral anticoagulation: a meta-analysis. Chin Med J 2013; 126(13):2536-42.

31. Khurram Z, Chou E, Minutello R, et al. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J Invasive Cardiol 2006; 18(4): 162-4.

32. Rubboli A, Milandri M, Castelvetri C, et al. Meta-analysis of trials comparing oral anticoagulation and aspirin versus dual antiplatelet therapy after coronary stenting. Clues for the management of patients with an indication for long-term anticoagulation undergoing coronary stenting. Cardiology 2005; 104(2): 101-6.doi: 10.1159/000086918.

33. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016; 375(25): 2423-34. doi:10.1056/NEJMoa1611594.

34. Mekaj YH, Daci FT, Mekaj AY. New insights into the mechanisms of action of aspirin and its use in the prevention and treatment of arterial and venous thromboembolism. Ther Clin Risk Manag 2015; 11: 1449-56. doi: 10.2147/TCRM.S92222.

35. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366(21): 1959-67. doi:10.1056/NEJMoa1114238.

36. Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367(21): 1979-87. doi:10.1056/NEJMoa1210384.

37. Kuijer PM, Hutten BA, Prins MH, et al. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999;159(5): 457-60. doi: 10.1001/archinte.159.5.457.

38. Ruíz-Giménez N, Suárez C, González R, et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100(1): 26-31. doi: 10.1160/TH08-03-0193.

39. Pisters R, Lane DA, Nieuwlaat R, et al. 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(5): 1093-100.doi: 10.1378/chest.10-0134.

40. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA(Anticoagulation and Risk Factors in Atrial Fibrillation)Study. J Am Coll Cardiol 2011; 58(4): 395-401. doi:10.1016/j.jacc.2011.03.031.

41. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF).Am Heart J 2006; 151(3): 713-9. doi: 10.1016/j.ahj.2005.04.017.

42. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149(2): 315-52. doi:10.1016/j.chest.2015.11.026.

43. Di Nisio M, Ageno W, Rutjes AW, et al. Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists. Thromb Haemost 2016; 115(2): 424-32. doi: 10.1160/TH15-06-0474.

44. Riva N, Bellesini M, Di Minno MN, et al. Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study. Thromb Haemost 2014; 112(3): 511-21. doi: 10.1160/TH14-01-0081.

45. Klok FA, Hosel V, Clemens A, et al. Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. Eur Respir J 2016; 48(5): 1369-76. doi: 10.1183/13993003.00280-2016.

46. Loewen P, Dahri K. Risk of bleeding with oral anticoagulants: an updated systematic review and performance analysis of clinical prediction rules. Ann Hematol 2011; 90(10): 1191-200. doi: 10.1007/s00277-011-1267-3.

47. Apostolakis S, Lane DA, Guo Y, et al. Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS(evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial fibrillation)study. J Am Coll Cardiol 2012; 60(9): 861-7. doi:10.1016/j.jacc.2012.06.019.

48. Zhu W, He W, Guo L, et al. The HAS-BLED Score for predicting major bleeding risk in anticoagulated patients with atrial fibrillation: a systematic review and meta-analysis. Clin Cardiol 2015; 38(9): 555-61. doi:10.1002/clc.22435.

49. Esteve-Pastor MA, Garcia-Fernandez A, Macias M, et al.Is the ORBIT bleeding risk score superior to the HASBLED score in anticoagulated atrial fibrillation patients?Circ J 2016; 80(10): 2102-8. doi: 10.1253/circj.CJ-16-0471.

50. Senoo K, Proietti M, Lane DA, et al. Evaluation of the HAS-BLED, ATRIA, and ORBIT bleeding risk scores in patients with atrial fibrillation taking warfarin. Am J Med 2016; 129(6): 600-7. doi: 10.1016/j.amjmed.2015.10.001.

51. Costa F, Tijssen JG, Ariotti S, et al. Incremental value of the CRUSADE, ACUITY, and HAS-BLED risk scores for the prediction of hemorrhagic events after coronary stent implantation in patients undergoing long or short duration of dual antiplatelet therapy. J Am Heart Assoc 2015; 4(12):pii: e002524. doi: 10.1161/JAHA.115.002524.