University of Wisconsin Hematology

Antithrombotic drugs

General

  1. Witt et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018;2:3257
  2. Guyatt et al. Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:7S
  3. Holbrook et al. Evidence-Based Management of Anticoagulant Therapy. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e152S
  4. Greineder et al. Advanced drug delivery systems for antithrombotic agents. Blood 2013;122:1565
  5. Yarrington et al. Cardiovascular Management in Pregnancy. Antithrombotic Agents and Antiplatelet Agents. Circulation 2015;132:1354
  6. Zhang et al. Use of D-dimer in oral anticoagulation therapy. Int J Lab Hematol 2018 (Epub)
  7. Palareti et al. D-dimer and reduced dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study. Blood Adv 20222 (Epub)  (D-dimer not useeful for decision-making in patients who have been anticoagulated for a year after VTE)
  8. Chan and Eikelboom. How I manage anticoagulant therapy in older individuals with atrial fibrillation or venous thromboembolism. Blood 2019;133:2269
  9. Abildgaard et al. Dosage of Anticoagulants in Obesity: Recommendations Based on a Systematic Review. Semin Thromb Hemost 2020;46: 932
  10. Pawar et al. Association of Type of Oral Anticoagulant Dispensed With Adverse Clinical Outcomes in Patients Extending Anticoagulation Therapy Beyond 90 Days After Hospitalization for Venous Thromboembolism. JAMA 2022;327:1051 (Somewhat lower VTE recurrence rate with apixaban vs warfarin; no differences in bleeding rates between apixaban, rivaroxaban and warfarin)
  11. Wang et al. Oral direct thrombin inhibitors or oral factor Xa inhibitors versus conventional anticoagulants for the treatment of deep vein thrombosis. Cochrane Database Syst Rev 2023;14;4:CD010956
  12. Li et al. Oral direct thrombin inhibitors or oral factor Xa inhibitors versus conventional anticoagulants for the treatment of pulmonary embolism. Cochrane Database Syst Rev 2023;14;4:CD010957
  13. Carlin et al. Anticoagulation for stroke prevention in atrial fibrillation and treatment of venous thromboembolism and portal vein thrombosis in cirrhosis: guidance from the SSC of the ISTH. J Thromb Haemost 2024;22:2653

Heparin, low molecular weight heparin and fondaparinux

  1. Hemker HC. A century of heparin: past, present and future. J Thromb Haemost 2016;14:2329
  2. Levy and Connors. Heparin resistance – clinical perspectives and management strategies. NEJM 2021;385:826
  3. de Swart et al.  Kinetics of intravenously administered heparin in normal humans. Blood 1982;60:1251
  4. Hanslik et al. Monitoring unfractionated heparin in children: a parallel-cohort randomized controlled trial comparing 2 dose protocols. Blood 2015;126:2091 (Anti-Xa assay correlated better with dose than ACT or aPTT)
  5. Padhya et al. Routine laboratory measures of heparin anticoagulation for children on extracorporeal membrane oxygenation: Systematic review and meta-analysis. Thromb Res 2019;179:132(Anti-Xa assay correlated best with heparin dose; assays did not predict bleeding well)
  6. Levy et al. What’s fishy about protamine? Clinical use, adverse reactions, and potential alternatives. J Thromb Haemost 2023;21:1714
  7. Garcia et al. Parenteral Anticoagulants. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e24S
  8. Gerotziafas et al. Effect of the anti‐factor Xa and anti‐factor IIa activities of low‐molecular‐weight heparins upon the phases of thrombin generation. J Thromb Haemost 2007;5:955
  9. Lim et al. Meta-Analysis: Low-Molecular-Weight Heparin and Bleeding in Patients with Severe Renal Insufficiency. Ann Intern Med 2006;144:673
  10. Douketis et al. Prophylaxis Against Deep Vein Thrombosis in Critically Ill Patients With Severe Renal Insufficiency With the Low-Molecular-Weight Heparin Dalteparin. An Assessment of Safety and Pharmacodynamics: The DIRECT Study. Arch Intern Med 2008;168:1805(dalteparin prophylaxis safe in severe renal failure)
  11. Greer and Nelson-Piercy. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401
  12. Patel et al. Population Pharmacokinetics of Enoxaparin During the Antenatal Period. Circulation 2013;128:1462(Half-life of enoxaparin prolonged in later pregnancy, once-daily administration may be appropriate)
  13. Avidan et al. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg 2005;130:107
  14. DeCarolis et al. Enoxaparin outcomes in patients with moderate renal imparment. Arch Intern Med 2012;172:1713(4.7-fold increased risk of major bleeding with CrCl 30-50)
  15. Kishimoto et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. NEJM 2008;358:2457
  16. Blossom et al. Outbreak of adverse reactions associated with contaminated heparin. NEJM 2008;359:2674
  17. Fox et al. Influence of Renal Function on the Efficacy and Safety of Fondaparinux Relative to Enoxaparin in Non–ST-Segment Elevation Acute Coronary Syndromes. Ann Intern Med 2007;147:304(Fondaparinux safer in patients with impaired renal function)
  18. Gouin-Thibault et  al. Tinzaparin, an alternative to subcutaneous unfractionated heparin, in patients with severe and end-stage renal impairment: a retrospective observational single-center study. J Thromb Haemost 2024;22:2864 (Drug does not accumulate in patients with ESRD)
  19. Eikelboom et al. Major Bleeding, Mortality, and Efficacy of Fondaparinux in Venous Thromboembolism Prevention Trials. Circulation 2009;120:2006
  20. Mazzolai et al. Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy. Blood 2006;108:1569
  21. Samama et al. Comparison of fondaparinux with low molecular weight heparin for venous thromboembolism prevention in patients requiring rigid or semi-rigid immobilization for isolated non-surgical below-knee injury. J Thromb Haemost 2013;11:1833(Fondaparinux 2.5 mg/d more effective than LMWH)
  22. Trujillo-Santos et al. Once versus twice daily enoxaparin for the initial treatment of acute venous thromboembolism. J Thromb Haemost 2017;15:429(Once-daily dosing associated with more VTE recurrence but less major bleeding and death)
  23. van Rein et al. Major bleeding risks of different low-molecular-weight heparin agents: a cohort study in 12 934 patients treated for acute venous thrombosis. J Thromb Haemost 2017;15:1386(Twice daily dosing associated with higher bleed risk)
  24. Miano et al. Comparative Effectiveness of Enoxaparin vs Dalteparin for Thromboprophylaxis After Traumatic Injury. Chest 2018;153:133(Dalteparin 5000 U once daily as effective as enoxaparin 30 mg bid)

Vitamin K antagonists

  1. Rishavy et al. Warfarin alters vitamin K metabolism: a surprising mechanism of VKORC1 uncoupling necessitates an additional reductase. Blood 2018;131:2826(A second, previously undescribed vitamin K reductase may contribute to warfarin resistance; with editorial)
  2. Ageno 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:e44S
  3. Björck et al. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiol 2016;1:172(“Well-managed warfarin therapy is associated with a low risk of complications”)
  4. Gage et al. Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee ArthroplastyA Randomized Clinical Trial. JAMA 2019;322:834(Target INR 1.8 resulted in higher rate of VTE or death than target 2.5)
  5. Osterberg and Blaschke.  Adherence to medication.  NEJM 2005;353:487
  6. Kimmel et al. The Influence of Patient Adherence on Anticoagulation Control With Warfarin. Results From the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study. Arch Intern Med 2007;167:229(36% of patients missed at least 20% of warfarin doses, with associated 2-fold increased risk of under-anticoagulation)
  7. Heneghan et al. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet 2012;379:322
  8. Oskarsdottir et al. Ignoring instead of chasing after coagulation factor VII during warfarin management: an interrupted time series study. Blood 2021;137:2745(Using PT variant only sensitive to factors II and X improved anticoaghulant control)
  9. White et al. Comparison of Outcomes Among Patients Randomized to Warfarin Therapy According to Anticoagulant Control. Results From SPORTIF III and V. Arch Intern Med 2007;167:239
  10. Shikata et al.  Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and -glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004;103:2630(much of the interpatient variation in warfarin sensitivity is genetic)
  11. Rieder et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.  NEJM 2005;352:2285
  12. Schwarz et al. Genetic Determinants of Response to Warfarin during Initial Anticoagulation. NEJM 2008;358:999(VKORC genotype is the major determinant of initial variability in response to warfarin)
  13. International Warfarin Pharmacogenetics Consortium. Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. NEJM 2009;360:753(pharmacogenetic algorithm better able to estimate therapeutic warfarin dose than clinical algorithm or fixed dose; see also the accompanying editorial)
  14. Wadelius et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009;113:784
  15. Eckman et al. Cost-Effectiveness of Using Pharmacogenetic Information in Warfarin Dosing for Patients With Nonvalvular Atrial Fibrillation. Ann Intern Med 2009;150:73
  16. Lenzini et al. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients. J Thromb Haemost 2008; 6:1655
  17. Gong et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood 2011;118:3163
  18. Anderson et al. A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II). Circulation 2012;125:1997(Better INR control and fewer adverse events using pharmacogenetic information to guide dosing)
  19. Kimmel et al. A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing. NEJM 2013;369:2283(Genotype-guided dosing did not improve anticoagulation control; with editorial)
  20. Pirmohamed et al. A randomized trial of genotype-guided dosing of warfarin. NEJM 2013;369:2294(Genotype-guided dosing did improve anticoagulation control; with editorial)
  21. Gage et al. Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty The GIFT Randomized Clinical Trial. JAMA 2017;318:1115(Less major bleeding, fewer episodes of over-anticoagulation with genotype-guided dosing; with editorial)
  22. Perera et al. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet 2013;382:790(Novel CYP2C polymorphism found in 25% of study population, associated with increased sensitivity to warfarin)
  23. De et al. Association of Genetic Variants With Warfarin-Associated Bleeding Among Patients of African Descent. JAMA 2018;320:1670
  24. Shahabi et al. An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance. Thromb Haemost 2016;116:2015
  25. Schulman et al. Warfarin Dose Assessment Every 4 Weeks Versus Every 12 Weeks in Patients With Stable International Normalized Ratios. A Randomized Trial. Ann Intern Med 2011;155:653(Every 12 weeks monitoring as safe as every 4 weeks for patients with stable INRs)
  26. Barnes et al. Extended International Normalized Ratio testing intervals for warfarin‐treated patients. J Thromb Haemost 2018;16:1307(Longer intervals for INR testing safe and effective in patients with stable INR)
  27. Zhang et al. D-dimer to guide the intensity of anticoagulation in Chinese patients after mechanical heart valve replacement: a randomized controlled trial. J Thromb Haemost 2017;15:1934(Adjusting intensity of anticoagulation according to D-dimer level associated with fewer adverse events)
  28. Schurgers et al. Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects. Blood 2004;104:2682
  29. de Assis et al. Improved Oral Anticoagulation After a Dietary Vitamin K–Guided Strategy. A Randomized Controlled Trial. Circulation 2009;120:1115(Modifying vit K intake according to INR improves anticoagulant control)
  30. Witt et al. Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood 2009;114:952(Less frequent monitoring may be appropriate for patients with stable INR control)
  31. Sconce et al. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood 2007;109:2419
  32. Theuwissen et al. Effect of low-dose supplements of menaquinone-7 (vitamin K2) on the stability of oral anticoagulant treatment: dose–response relationship in healthy volunteers. J Thromb Haemost 2013;11:1085(Very low doses of vit K2 can affect INR; study does not really address stability)
  33. Boonyawat et al. The effect of low-dose oral vitamin K supplementation on INR stability in patients receiving warfarin. A randomised trial. Thromb Haemost 2016;116:403(Vit K 150 mcg/d improved INR stability)
  34. Conway et al. Suppression of Hemostatic System Activation by Oral Anticoagulants in the Blood of Patients with Thrombotic Diatheses. J Clin Invest 1987;80:1535
  35. Schulman S.  Care of patients receiving long-term anticoagulant therapy.  NEJM 2003;349:675
  36. Matchar et al. Effect of Home Testing of International Normalized Ratio on Clinical Events. NEJM 2010;363:1608
  37. Dlott et al. National Assessment of Warfarin Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation. Circulation 2014;129:1407(Mean time in therapeutic range arounc 53%)
  38. Linkins et al.  Clinical Impact of Bleeding in Patients Taking Oral Anticoagulant Therapy for Venous Thromboembolism. A meta-analysis. Ann Intern Med 2003;139:893
  39. Wysowski et al Bleeding complications with warfarin use. A prevalent adverse effect resulting in regulatory action. Arch Intern Med 2007;167:1414
  40. Levi et al. Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based. Blood 2008;111:4471(bleeding risk from VKAs in “real life” likely to be higher than that reported in clinical trials)
  41. Dargaud et al. Bleeding risk in warfarinized patients with a therapeutic international normalized ratio: the effect of low factor IX levels. J Thromb Haemost 2013;11:1043
  42. Poli et al. The predictive ability of bleeding risk stratification models in very old patients on vitamin K antagonist treatment for venous thromboembolism: results of the prospective collaborative EPICA study. J Thromb Haemost 2013;11:1053(Major bleeding rate 2.4/100 pt-yrs; risk stratification models not accurate in patients over 80)
  43. Dunn and Turpie. Perioperative Management of Patients Receiving Oral Anticoagulants. A Systematic Review. Arch Intern Med. 2003;163:901
  44. Odén et al. Oral anticoagulation and risk of death: a medical record linkage study. BMJ 2002;325:1073
  45. Holbrook et al. Systematic Overview of Warfarin and Its Drug and Food Interactions. Arch Intern Med 2005;165:1095
  46. Clark et al. Warfarin Interactions With Antibiotics in the Ambulatory Care Setting. JAMA Intern Med 2014;174:409
  47. Schalekamp et al. Increased Bleeding Risk With Concurrent Use of Selective Serotonin Reuptake Inhibitors and Coumarins. Arch Intern Med 2008;168:180
  48. Quinn et al. Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial. J Am Heart Assoc 2018;7:e008755(No significant increase in bleeding risk when SSRI used together with DOAC; minimal increase in risk with SSR+warfarin)
  49. Lopes et al. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility. Blood 2011;118:6269
  50. Haaland et al. Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years. JAMA Intern Med 2017;177:1774
  51. Warkentin et al. Warfarin-induced venous limb ischemia/gangrene complicating cancer: a novel and clinically distinct syndrome. Blood 2015;126:486
  52. Wheeler et al. Anticoagulation-related nephropathy. J Thromb Haemost 2016;14:461
  53. Veronese et al. Vitamin K antagonists’ use and fracture risk: results from a systematic review and meta-analysis. J Thromb Haemost 2015;13:1665(No clear evidence of an adverse effect of VKAs on bone health)
  54. Lau et al. Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation. JAMA 2017;317:1151(Higher risk of fracture with warfarin treatment)

Antiplatelet drugs

  1. Eikelboom et al. Antiplatelet Drugs. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e89S
  2. Weitz et al. New Antithrombotic Drugs. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e120S
  3. Stanger et al. Antiplatelet strategies: past, present, and future. J Thromb Haemost 2023;21:3317
  4. Kaplan and Jackson. The role of platelets in atherothrombosis. Hematology 2011:51
  5. Michelson AD. Advances in antiplatelet therapy. Hematology 2011:62
  6. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease. US Preventive Services Task Force Recommendation Statement. JAMA 2022;327:1577 (Recommends against routine ASA prophylaxis)
  7. Jones et al. Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease. NEJM 2021;384:1981(No difference in outcomes between 81 mg and 325 mg daily)
  8. Joseph et al. Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis. Lancet 2021;398:1133 (Adding ASA reduced incidence of cardiovascular events)
  9. Li et al. Reversal of the anti-platelet effects of aspirin and clopidogrel. J Thromb Haemost 2012;10:521(Normalization of in vitro platelet aggregation occurs 4 days after stopping aspirin, but takes 10 days after stopping clopidogrel)
  10. Saito et al. Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus. 10-Year Follow-Up of a Randomized Controlled Trial. Circulation 2017;135:659(ASA did not reduce cardiovascular risk but did increase bleeding in Japanese patients)
  11. McNeil et al. Effect of Aspirin on Disability-free Survival in the Healthy Elderly. NEJM 2018;379:1499(No survival benefit, more major bleeding with ASA)
  12. McNeil et al. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. NEJM 2018;379:1509(No difference in cardiovascular events, more major bleeding with ASA; with editorial)
  13. McNeil et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. NEJM 2018;379:1519(ASA associated with higher all-cause mortality, more cancer deaths; with editorial)
  14. Selak et al. Predicting Bleeding Risk to Guide Aspirin Use for the Primary Prevention of Cardiovascular Disease: A Cohort Study. Ann Intern Med 2019;170:357
  15. McQuilten et al. Effect of Low-Dose Aspirin Versus Placebo on Incidence of Anemia in the Elderly. A Secondary Analysis of the Aspirin in Reducing Events in the Elderly Trial. Ann Intern Med 2023;176:913 (Low dose ASA increased incidence of anemia and iron deficiency)
  16. Undas et al. Why does aspirin decrease the risk of venous thromboembolism? On old and novel antithrombotic effects of acetyl salicylic acid. J Thromb Haemost 2014;12:1776
  17. Glynn et al. Effect of low-dose aspirin on the occurrence of venous thromboembolism. Ann Intern Med 2007;147:525(ASA 100 mg qod had no apparent effect on occurence of VTE in women)
  18. Simes et al Aspirin for the Prevention of Recurrent Venous Thromboembolism. The INSPIRE Collaboration. Circulation 2014;130:1062(ASA reduces recurrence rate by about one-third, does not increase bleeding risk; with editorial)
  19. Cavallari et al. Frequency, Predictors, and Impact of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients With Symptomatic Atherosclerosis.  Circulation 2018;137:684
  20. Berger et al. Aspirin for the Primary Prevention of Cardiovascular Events in Women and Men. A Sex-Specific Meta-analysis of Randomized Controlled Trials. JAMA 2006;295:306
  21. Campbell et al. Aspirin Dose for the Prevention of Cardiovascular Disease: A Systematic Review. JAMA 2007;297:2018(81 mg/d is enough)
  22. Xian et al. Association of Discharge Aspirin Dose With Outcomes After Acute Myocardial Infarction. Insights From the Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) Study. Circulation 2105;132:174(Low-dose ASA as effective as high-dose, with less bleeding)
  23. Seshasai et al. Effect of aspirin on vascular and nonvascular outcomes. Meta-analysis of randomized controlled trials. Arch Intern Med 2012;172:209(“Aspirin prophylaxis in people without prior cardiovascular disease does not lead to reductions in either cardiovascular death or cancer mortality”)
  24. Chan et al. Long-term aspirin use and mortality in women. Arch Intern Med 2007;167:562
  25. Devereaux et al. Aspirin in patients undergoing noncardiac surgery. NEJM 2014;370:1494(No significant decrease in death or MI, increased risk of major bleeding)
  26. Graham et al. Aspirin in Patients With Previous Percutaneous Coronary Intervention Undergoing Noncardiac Surgery. Ann Intern Med 2018;168:237(“Aspirin use may be more likely to benefit than harm patients”)
  27. Palmer et al. Effects of Antiplatelet Therapy on Mortality and Cardiovascular and Bleeding Outcomes in Persons With Chronic Kidney Disease. A Systematic Review and Meta-analysis.Ann Intern Med 2012;156:445(No clear evidence of benefit)
  28. Polzin et al. Antiplatelet effects of aspirin in chronic kidney disease patients. J Thromb Haemost 2016;14:375 (CKD decreases antiplatelet response to ASA)
  29. Koo et al. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial. Lancet 2021;397:2487 (Clopidogrel superior)
  30. Angiolillo et al. International Expert Consensus on Switching Platelet P2Y12 Receptor–Inhibiting Therapies. Circulation 2017;136:1955
  31. Eshaghian et al. Role of clopidogrel in managing atheroembolic cardiovascular disease. Ann Intern Med 2007;146:434
  32. Gurbel et al. Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease. The ONSET/OFFSET Study. Circulation 2009;120:2577
  33. Roe et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. NEJM 2012;367:1297
  34. Gerrits et al. Incomplete reversibility of platelet inhibition following prolonged exposure to ticagrelor. J Thromb Haemost 2017;15:858
  35. James et al. Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack. Circulation 2012;125:2914(Higher rate of intracranial bleeding with ticagrelor)
  36. Gimbel et al. Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label, non-inferiority trial. Lancet 2020;395:1374 (Clopidogrel safer in older patients)
  37. Hiatt et al. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. NEJM 2017;376:32(No significant difference in safety or efficacy)
  38. Schüpke et al.Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. NEJM 2019;381:1524(Prasugrel more effective, with similar bleeding risk)
  39. Bonaca et al. Long-term use of ticagrelor in patients with prior myocardial infarction. NEJM 2015;372:1791(Ticagrelor reduced risk of MI, stroke or cardiovascular death but increased risk of major bleeding; with editorial)
  40. Easton et al. Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes). Circulation 2017;136:907(Incidence of major bleeding not different with ticagrelor vs ASA)
  41. Mehran et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. NEJM 2019;381:2032(Ticagrelor alone safer, equally effective)
  42. Sandner et al. Association of Dual Antiplatelet Therapy With Ticagrelor With Vein Graft Failure After Coronary Artery Bypass Graft Surgery.  A Systematic Review and Meta-analysis. JAMA 2022;328:554 (Less graft failure, more bleeding with adding ticagrelor)
  43. Motovska et al. Prasugrel Versus Ticagrelor in Patients With Acute Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention. Multicenter Randomized PRAGUE-18 Study. Circulation 2016;134:1603(No difference in outcomes)
  44. Steg et al. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. NEJM 2019;381:1309 (10% decrease in ischemic events with ticagrelor + ASA, twice as much bleeding vs ASA alone; with editorial)
  45. Turgeon et al. Association of Ticagrelor vs Clopidogrel With Major Adverse Coronary Events in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention. JAMA Intern Med 2020;180:420 (Ticagrelor did not lower coronary event rate but did increase bleeding risk)
  46. Wang et al. Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA. NEJM 2021;385:2520 (Modest reduction in stroke risk with ticagrelor)
  47. Wang et al. Ticagrelor–Aspirin Versus Clopidogrel–Aspirin Among CYP2C19 Loss-of-Function Carriers With Minor Stroke or Transient Ischemic Attack in Relation to Renal Function: A Post Hoc Analysis of the CHANCE-2 Trial. Ann Intern Med 2022;175:1534 (Benefit of ticagrelor in above trial restricted to those with normal renal function)
  48. Szummer et al. Comparison Between Ticagrelor and Clopidogrel in Elderly Patients With an Acute Coronary Syndrome. Insights From the SWEDEHEART Registry. Circulation 2020;142:1700 (More bleeding, higher mortality with ticagrelor)
  49. O’Donoghue et al. Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention. Insights From the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) Trial. Circulation 2016;133:248(Cangrelor reduced rate of death, MI and other vascular complications vs clopidogrel without an increase in rate of major bleeding)
  50. Bhatt et al. Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events. NEJM 2013;368:1303(Cangrelor + ASA arm had fewer ischemic events than clopidogrel + ASA arm, no increased bleeding; with editorial)
  51. Angiolillo et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery. A randomized controlled trial. JAMA 2012;307:265
  52. Piccolo et al. Use of the Dual-Antiplatelet Therapy Score to Guide Treatment Duration After Percutaneous Coronary Intervention. Ann Intern Med 2017; 167:17
  53. O’Donoghue et al. The Safety and Efficacy of Aspirin Discontinuation on a Background of a P2Y12 Inhibitor in Patients After Percutaneous Coronary Intervention.  A Systematic Review and Meta-Analysis. Circulation 2020;142:538 (Stopping ASA 1-3 mo after PCI reduces bleeding risk, does not increase coronary risk)
  54. Khan et al. Dual Antiplatelet Therapy After Percutaneous Coronary Intervention and Drug-Eluting Stents. A Systematic Review and Network Meta-Analysis. Circulation 2020;142:1425
  55. Fries and Grosser. The Cardiovascular Pharmacology of COX-2 Inhibition. Hematology 2005:445-451
  56. Solomon et al. Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas. Circulation 2006;114:1028(nearly 2-fold increase in cardiovascular risk)
  57. Haag et al. Cyclooxygenase Selectivity of Nonsteroidal Anti-inflammatory Drugs and Risk of Stroke. Arch Intern Med 2008;168:1219(Increased risk with both nonselective and COX-2 selective NSAIDs)
  58. Künze and Isermann. Targeting biased signaling by PAR1: function and molecular mechanism of parmodulins. Blood 2023:141:2684
  59. Tricoci et al. Thrombin-receptor antagonist voraxapar in acute coronary syndromes. NEJM 2012;366:20 (Treatment had no effect on death from cardiovascular events, but increased bleeding risk)
  60. Morrow et al. Vorapaxar in the Secondary Prevention of Atherothrombotic Events. NEJM 2012;366:1404 (Some reduction of cardiovascular events in treatment group, but increased risk of severe bleeding and intracranial hemorrhage)
  61. Scrica et al. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial. Lancet 2012;380:1317  (Lower risk of death or ischemic events, more major bleeding with voraxapar)
  62. Cavender et al. Vorapaxar in Patients With Diabetes Mellitus and Previous Myocardial Infarction. Findings From the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 Trial. Circulation 2015;131:1047 (Significant overall benefit of vorapaxar in high risk patients)
  63. Bohula et al. Efficacy and Safety of Vorapaxar With and Without a Thienopyridine for Secondary Prevention in Patients With Previous Myocardial Infarction and No History of Stroke or Transient Ischemic Attack. Results from TRA 2°P-TIMI 50 (Vorapaxar reduced rates of cardiac death, MI and stroke, with an increased risk of moderate or severe bleeding)
  64. Malehmir et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med 2019;25:641 (Platelet activation increased in NASH, antiplatelet Rx prevents NASH and HCC)

Antiplatelet drug resistance/monitoring

  1. Galli et al. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Lancet 2021;397:1470 (Drug selection guided by genotype or functional testing slightly reduced major cardiac events and bleeding)
  2. Frelinger et al. Laboratory monitoring of P2Y12 inhibitors: communication from the SSC of the ISTH. J Thromb Haemost 2018;16:2341
  3. Mahla et al. Is There a Role for Preoperative Platelet Function Testing in Patients Undergoing Cardiac Surgery During Antiplatelet Therapy?. Circulation 2018;138:2145
  4. Michelson and Bhatt. How I use laboratory monitoring of antiplatelet therapy. Blood 2017;130:713
  5. Sanderson et al.  Narrative Review: Aspirin Resistance and Its Clinical Implications.  Ann Intern Med 2005;142:370
  6. Undas et al. Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood 2007; 109:2285
  7. Grosser et al Drug Resistance and Pseudoresistance. An Unintended Consequence of Enteric Coating Aspirin. Circulation 2013;127:377(True aspirin resistance is rare; “pseudoresistance” found with enteric-coated ASA)
  8. Cattneo M. The clinical relevance of response variabilitiy to antiplatelet therapy. Hematology 2011:70
  9. Nührenberg et al. Temporal variability in the antiplatelet effects of clopidogrel and aspirin after elective drug-eluting stent implantation. Thromb Haemost 2015;114:1020
  10. Wisman et al. Platelet-reactivity tests identify patients at risk of secondary cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost 2014;12:736
  11. Shuldiner et al. Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy. JAMA 2009;302:849
  12. Mega et al. Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated With Clopidogrel Predominantly for PCI. A Meta-analysis JAMA 2010;304:1821(with editorial)
  13. Pan et al. Genetic Polymorphisms and Clopidogrel Efficacy for Acute Ischemic Stroke or Transient Ischemic Attack A Systematic Review and Meta-Analysis. Circulation 2017;135:21(CYP2C19 loss-of-function alleles incresed risk of vascular events after stroke or TIA in clopidogrel-treated patients)
  14. Liang et al. Active metabolite concentration of clopidogrel in patients taking different doses of aspirin: results of the interaction trial. J Thromb Haemost 2015;13:347(Blood levels affected by genotype, BMI, diabetes, PPI, and renal function, not by ASA use)
  15. Price et al. Standard- vs High-Dose Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention: The GRAVITAS Randomized Trial. JAMA 2011;305:1061(No apparent benefit from high dose clopidogrel in patients with high on-treatment platelet reactivity)
  16. Mega et al. Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease. JAMA 2011;306:2221(Tripling drug dose effective for CYP2C19*2 heterozygotes but not homozygotes)
  17. Classens et al. A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI. NEJM 2019;381:1621
  18. Parodi et al. High Residual Platelet Reactivity After Clopidogrel Loading and Long-term Cardiovascular Events Among Patients With Acute Coronary Syndromes Undergoing PCI. JAMA 2011;306:1215(Clopidogrel resistance in vitro associated with higher incidence of subsequent vascular events)
  19. Tang et al. Randomized Comparisons of Double-Dose Clopidogrel or Adjunctive Cilostazol Versus Standard Dual Antiplatelet in Patients With High Posttreatment Platelet ReactivityCirculation 2018;137:2231
  20. Stone et al. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet 2013;382:614
  21. Collet et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. NEJM 2012;367:2100(No apparent benefit to increasing clopidogrel dose in patients with in vitro clopidogrel resistance)
  22. Gurbel et al. Platelet Function During Extended Prasugrel and Clopidogrel Therapy for Patients With ACS Treated Without Revascularization. The TRILOGY ACS Platelet Function Substudy. JAMA 2012;308:1785(More effective in vitro platelet inhibition by prasugrel vs clopidogrel not associated with better outcomes)
  23. Montalescot et al. High On-Treatment Platelet Reactivity as a Risk Factor for Secondary Prevention After Coronary Stent Revascularization. A Landmark Analysis of the ARCTIC Study. Circulation 2014;129;2136(Adjusting antiplatelet therapy based on platelet function tests did not reduce recurrent ischemic events after stenting; with editorial)
  24. Cayla et al. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016;388:2015(No apparent benefit to adjusting antiplatelet drug doses based on lab tests)
  25. Bonello et al. Relationship between post-treatment platelet reactivity and ischemic and bleeding events at 1-year follow-up in patients receiving prasugrel. J Thromb Haemost 2012;10:1999
  26. Wang et al. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA 2016;316:70(Benefit of clopidogrel limited to patients who do not carry loss-of-function allele)
  27. Perl et al. Response to Prasugrel and Levels of Circulating Reticulated Platelets in Patients With ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol 2014;63:513(High immature platelet fraction causes prasugrel resistance)
  28. Kazi et al. Cost-Effectiveness of Genotype-Guided and Dual Antiplatelet Therapies in Acute Coronary Syndrome. Ann Intern Med 2014;160:221
  29. Ho et al. Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome. JAMA 2009;301:937
  30. Rossini et al. Perioperative management of oral antiplatelet therapy and clinical outcomes in coronary stent patients undergoing surgery. Thromb Haemost 2015;113:221(Stopping antiplatelet drugs increases risk of adverse cardiac events, does not reduce bleeding risk)

Direct thrombin and Xa inhibitors (DOACs)

General

  1. Yeh et al. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood 2014;124:1020
  2. Ageno 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:e44S
  3. Weitz et al. New Antithrombotic Drugs. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e120S
  4. Ageno et al. Selection and assessment of patients treated with the novel oral anticoagulant drugs: a recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2013;11:177
  5. Raymond et al. Pharmacogenetics of Direct Oral Anticoagulants: A Systematic Review. J Pers Med 2021;11:37
  6. Aronis and Hylek. Evidence Gaps in the Era of Non–Vitamin K Oral Anticoagulants. J Am Heart Assoc 2018;7:e007338
  7. Lowenstern et al. Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review. Ann Intern Med 2018;169:774(DOACs “at least as effective and safe as warfarin”; apixaban seems superior to others)
  8. Testa et al. Low drug levels and thrombotic complications in high‐risk atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost 2018;16:842(Low trough levels of DOACs associated with higher thrombotic risk)
  9. Carter et al. Rivaroxaban and apixaban induce clotting factor Xa fibrinolytic activity. J Thromb Haemost 2018;16:2276
  10. Raval et al. Management of Patients on Non–Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association. Circulation 2017;135:e604
  11. Abildgaard et al. Dosage of Anticoagulants in Obesity: Recommendations Based on a Systematic Review. Semin Thromb Hemost 2020;46: 932
  12. Carlin and Eikelboom. Direct oral anticoagulant dose selection: Challenging cases. J Thromb Haemost 2021;19:2680
  13. Chai-Adisaksopha et al. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015;13:2012(Less fatal bleeding, lower case-fatality rate for major bleeding, less cardiovascular mortality and lower all-cause mortality with DOACs vs warfarin)
  15. Yui et al. Arthrocentesis and Joint Injection in Patients Receiving Direct Oral Anticoagulants. Mayo Clin Proc 2017;92:1176 (These procedures safe in patients on DOACs, no need to withhold drug prior)
  16. Berkowitz and Moll. Athletes and blood clots: individualized, intermittent anticoagulation management. J Thromb Haemost 2017;15:1051(Potential role of DOACs in treating athletes involved in contact sports)
  17. Hakeam et al. Direct Acting Oral Anticoagulants Following Gastrointestinal Tract Surgery. J Cardiovasc Pharmacol 2021;78:867

VTE treatment

  1. van der Hulle 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;12:320(Comparable efficacy to warfarin, somewhat lower risk of bleeding)
  2. van Es et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014;124:1968(Similar effficacy, less bleeding with new agents)
  3. Mai et al. Extended Anticoagulation for VTE: A Systematic Review and Meta-Analysis. Chest 2019;155:1199(DOACs reduce overall mortality vs observation alone)
  4. Ibrahim et al. Efficacy and safety of reduced-dose versus full-dose direct oral anticoagulants for extended treatment of venous thromboembolism: A meta-analysis with trial sequential analysis and reconstructed time-to-event data. Thromb Res 2025;254:10296 (Reduced-dose regimens effective, safer than full-dose)
  5. Palareti et al. D-dimer and reduced dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study. Blood Adv 20222 (Epub)  (D-dimer not useeful for decision-making in patients who have been anticoagulated for a year after VTE)
  6. Vasanthamohan et al. Reduced‐dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2018;16:1288(Reduced dose DOACs as effective as full dose, with bleeding risk similar to placebo)
  7. Janczak et al. Rivaroxaban and Apixaban for Initial Treatment of Acute Venous Thromboembolism of Atypical Location. Mayo Clin Proc 2018; 93:40(Efficacy and safety similar to that in patients with VTE in typical locations)
  8. Cohen et aL. Use of direct oral anticoagulants in antiphospholipid syndrome. J Thromb Haemost 2018;16:1028
  9. Kovac et al. The use of direct oral anticoagulants in the secondary prevention of venous thromboembolism in patients with severe thrombophilia: communication from the ISTH SSC Subcommittee on Physiological Anticoagulants and Thrombophilia. J Thromb Haemost 2024;22:3322
  10. Bellin et al. New oral anti-coagulants versus vitamin K antagonists in high thromboembolic risk patients. PLoS One 2019;14::e0222762(DOAC use associated with fewer ischemic events and less bleeding than warfarin in AF patients in this retrospective study)
  11. Huang et al. Risk of Osteoporosis in Patients With Atrial Fibrillation Using Non–Vitamin K Antagonist Oral Anticoagulants or Warfarin. J Am Heart Assoc 2020 (Epub)(Apixaban and rivaroxaban associated with lower risk than warfarin)
  12. Lutsey et al. Association of Anticoagulant Therapy With Risk of Fracture Among Patients With Atrial Fibrillation. JAMA Intern Med 2020;180:245(Moderate reduction in fracture risk with DOACs – particularly apixaban – vs warfarin)
  13. Lau et al.Association Between Treatment With Apixaban, Dabigatran, Rivaroxaban, or Warfarin and Risk for Osteoporotic Fractures Among Patients With Atrial Fibrillation. A Population-Based Cohort Study. Ann Intern Med 2020;173:1(DOACs associated with lower fracture risk than warfarin)
  14. Klok et al.Early switch to oral anticoagulation in patients with acute intermediate-risk pulmonary embolism (PEITHO-2): a multinational, multicentre, single-arm, phase 4 trial. Lancet Haematol 2021;8:e627(Switching to dabigatran after 72 h of LMWH or UFH was effective and safe)

VTE prophylaxis

  1. Liew et al. Extended-duration new oral anticoagulants for venous thromboprophylaxis in patients undergoing total hip arthroplasty: a meta-analysis of the randomized controlled trials. J Thromb Haemost 2014;12:107(60% reduction in VTE risk, no increase in major bleeding with NOACs vs LMWH)
  2. Neumann et al. Oral Direct Factor Xa Inhibitors Versus Low-Molecular-Weight Heparin to Prevent Venous Thromboembolism in Patients Undergoing Total Hip or Knee Replacement. A Systematic Review and Meta-analysis. Ann Intern Med 2012;156:710
  3. Adam et al. Comparative Effectiveness of New Oral Anticoagulants and Standard Thromboprophylaxis in Patients Having Total Hip or Knee Replacement: A Systematic Review. Ann Intern Med 2013;159:275

Atrial fibrillation

  1. Carnicelli et al. Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex. Circulation 2022 (Epub)
  2. Sharma et al. Efficacy and Harms of Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism. Systematic Review and Meta-Analysis. Circulation 2015;132:194(Efficacy of NOACs at least as good as warfarin in patients > 75, with different bleeding patterns; higher GI bleed risk with dabigatran)
  3. Lega et al . Consistency of safety and efficacy of new oral anticoagulants across subgroups of patients with atrial fibrillation. PLoS One 2014; 9:e91398(“NOAC appeared to be more effective and safer than VKA … irrespective of patient comorbidities”)
  4. Chao et al. Oral Anticoagulation in Very Elderly Patients With Atrial Fibrillation. A Nationwide Cohort Study. Circulation 2018;138:37 (DOACs still preferred in patients >90)
  5. Adam et al. Comparative Effectiveness of Warfarin and New Oral Anticoagulants for the Management of Atrial Fibrillation and Venous Thromboembolism: A Systematic Review. Ann Intern Med 2012;157:796
  6. Vene et al. Risk of Thromboembolic Events in Patients with Non-Valvular Atrial Fibrillation After Dabigatran or Rivaroxaban Discontinuation – Data from the Ljubljana Registry. PLOS One2016;11:e0156943(Stopping DOAC associated with 20-fold increase in the short-term risk of thromboembolism; peak incidence about 14 days after stopping)
  7. Lee et al. Risk of Myocardial Infarction in Anticoagulated Patients With Atrial Fibrillation. J Am Coll Cardiol 2018;72:17(Lower risk of MI in DOAC users than warfarin users, no difference among DOACs)
  8. Lopes et al. Effectiveness and Safety of Anticoagulants in Adults with Non-valvular Atrial Fibrillation and Concomitant Coronary/Peripheral Artery Disease. Am J Med 2018 (Epub)(Survey of Medicare population; All DOACs associated with lower stroke, MI and mortality risk vs warfarin; apixaban caused less bleeding)
  9. Dawwas et al. Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation A Population-Based Cohort Study. Ann Intern Med 2021;174:920(DOACs safer and more effective than warfarin; apixaban had best safety and efficacy)
  10. Itzhaki et al. Risk of stroke and other thromboembolic complications after interruption of DOAC therapy compared with warfarin therapy in patients with atrial fibrillation: a retrospective cohort analysis. J Investig Med 2021 (Epub)(No difference in complication rate)
  11. Bennaghmouch et al. Efficacy and Safety of the Use of Non–Vitamin K Antagonist Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation and Concomitant Aspirin Therapy. A Meta-Analysis of Randomized Trials.  Circulation 2018;13t:1117
  12. Connolly et al. Rivaroxaban in Rheumatic Heart Disease–Associated Atrial Fibrillation. NEJM 2022;387:978 (INVICTUS trial. Better outcomes with VKA. With editorial)
  13. Hayes et al. Benefits and Harms of Standard Versus Reduced‐Dose Direct Oral Anticoagulant Therapy for Older Adults With Multiple Morbidities and Atrial Fibrillation. J Am Heart Assoc 2023 (Epub) (Low dose DOACs effective, caused less bleeding)
  14. Lip et al. Comparative safety and effectiveness of oral anticoagulants in patients with non-valvular atrial fibrillation and high risk of gastrointestinal bleeding: A nationwide French cohort study. PLOS One 2024;19(11):e0310322 (Apixaban superior to VKAs and other DOACs)
  15. Patil et al. Evaluating the safety and effectiveness of direct oral anticoagulants compared with warfarin in very elderly patients with atrial fibrillation with and without low bodyweight. J Thromb Haemost 2024;22:3107 (DOACs appear safer and more effective than warfarin in pts age 80+ regardless of body weight in this retrospective study)
  16. Dawwas et al. Direct Oral Anticoagulants Compared With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease Without Mechanical Valves. J Am Heart Assoc 2025 (Epub)

DOACs in kidney disease

  1. Harrington et al. Direct Oral Anticoagulants Versus Warfarin Across the Spectrum of Kidney Function: Patient-Level Network Meta-Analyses From COMBINE AF. Circulation 2023 (Epub) (“Standard-dose DOACs are safer and more effective than warfarin down to a CrCl of at least 25 mL/min. Lower-dose DOACs do not significantly lower the incidence of bleeding or ICH compared with standard-dose DOACs but are associated with a higher incidence of stroke/embolism and death”)
  2. Pokorney et al. Apixaban for Patients with Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial. Circulation 2022 (Epub) (No difference in outcomes between apixaban and VKA in this rather small trial)
  3. Reinecke et al. A Randomized Controlled Trial Comparing Apixaban to the Vitamin K-antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 study. Circulation 2022 (Epub) (No difference in outcomes – small trial)
  4. Derebail et al. Role of direct oral anticoagulants in patients with kidney disease. Kidney Int 2020 (Epub)
  5. Ashley et al. Risk of Cardiovascular Events and Mortality Among Elderly Patients With Reduced GFR Receiving Direct Oral Anticoagulants. Am J Kidney Dis 2020 (Epub) (Lower risk of cardiovascular events or death with DOACs vs warfarin, particularly in those with eGFR < 30)
  6. Wetmore et al. Direct-Acting Oral Anticoagulants Versus Warfarin in Medicare Patients With Chronic Kidney Disease and Atrial Fibrillation. Stroke 2020 (Epub)(Apixaban safer and more effective than VKA or other DOACs in CKD stage 3-5)
  7. Wetmore et al. Apixaban versus Warfarin for Treatment of Venous Thromboembolism in Patients Receiving Long-Term Dialysis. Clin J Am Soc Nephrol 2022;17:693 (Apixaban had better efficacy and safety than warfarin)
  8. Wetmore et al. Apixaban Dosing Patterns Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation Receiving Dialysis: A Retrospective Cohort Study. Am J Kidney Dis 2022 (Epub) (Reduced apixaban dosing not necessary in dialysis patients)
  9. Xu et al. Associations of Apixaban Dose With Safety and Effectiveness Outcomes in Patients With Atrial Fibrillation and Severe Chronic Kidney Disease. Circulation 2023 (Epub) (Low dose apixaban safer, equally effective)
  10. Ofek et al. International Normalized Ratio Is Significantly Elevated With Rivaroxaban and Apixaban Drug Therapies: A Retrospective Study. Clin Ther 2017;39:1003(Both drugs prolong the INR, rivaroxabn moreso)
  11. Pastori et al. Association of different oral anticoagulants use with renal function worsening in patients with atrial fibrillation: A multicentre cohort study. Br J Clin Pharmacol 2020(Epub) (DOACs associated with less decline in eGFR than warfarin)
  12. Gurevitz et al. Comparison of Low and Full Dose Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Renal Dysfunction (from a National Registry).Am J Cardiol 2021 (Epub)(Better overall outcomes with apixaban than with warfarin)
  13. Fung et al. Pharmacokinetics of Apixaban Among Peritoneal Dialysis Patients. Kidney Med 2023;5:100646 (AUC higher than in HD patients, recommend monitoring levels)
  14. Fu et al. Comparative Safety and Effectiveness of Warfarin or Rivaroxaban Versus Apixaban in Patients With Advanced CKD and Atrial Fibrillation: Nationwide US Cohort Study. Am J Kidney Dis 2023 (Epub) (Less bleeding with apixaban than with warfarin or rivaroxaban)
  15. Kao et al. Anticoagulation for Patients With Concomitant Atrial Fibrillation and End-Stage Renal Disease: A Systematic Review and Network Meta-Analysis. J Am Heart Assoc 2024;13:e034176
  16. Ko et al. A randomized controlled trial evaluated the efficacy and safety of apixaban for prevention of recurrent thrombosis after thrombectomy of hemodialysis vascular access. Kidney Int 2024 (Epub) (Apixaban reduced access thrombosis rate from 40% to 24%, with no increase in mortality or major bleeding)
  17. Du et al. Oral anticoagulant therapy for patients with atrial fibrillation on long-term dialysis: A network meta-analysis of 137,574 patients. Eur J Clin Invest 2025 (Epub) (Apixaban 5 mg bid lowered overall mortality; other regimens did not)

DOACs in liver disease

  1. Lawal et al. Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study. Circulation 2023 (Epub) (Apixaban caused less bleeding than warfarin or rivaroxaban)
  2. Simon et al. Comparative Effectiveness and Safety of Apixaban, Rivaroxaban, and Warfarin in Patients With Cirrhosis and Atrial Fibrillation: A Nationwide Cohort Study. Ann Intern Med 2024 (Epub) (Apixaban safer than rivaroxaban or warfarin)

DOACs in obese patients

  1. Martin et al. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost 2021;19:1874
  2. Wang and Carrier. How I treat obese patients with oral anticoagulants. Blood 2020;135:904
  3. Lip et al. Short-Term Outcomes of Apixaban Versus Warfarin in Patients With Atrial Fibrillation. Is Body Weight an Important Consideration? Circulation 2019;139:2301 (Summary of RCT data on DOACs in obese patients)
  4. Dobry et al. Treatment of atrial fibrillation and venous thromboembolism with factor Xa inhibitors in severely obese patients. J Thromb Haemost 2024;22:3500 (Apixaban & rivaroxaban safe & effective vs warfarin in patients with BMI >50 or weight >1`50 kg)
  5. Kushnir et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haematol 2019 (Epub)(Apixaban and rivaroxaban as effective as warfarin in patients with BMI over 40)
  6. Coons et al. Effectiveness and Safety of Direct Oral Anticoagulants versus Warfarin in Obese Patients with Acute Venous Thromboembolism. Pharmacotherapy 2020 (Epub)(DOACs as effective and safe as warfarin in this fairly large study)
  7. Cohen et al. Effectiveness and Safety of Apixaban vs. Warfarin in Venous Thromboembolism Patients with Obesity and Morbid Obesity. J Clin Med 2021;10:E200(Apixaban associated with lower rates of recurrent VTE and major bleeding than warfarin; data from healthcare claims databases)
  8. Chin-Hon et al. Safety and efficacy of oral anticoagulants in extreme weights.  Thromb Res 2023;231:1 (Apixaban has best safety & efficacy)
  9. Leong et al. Direct oral anticoagulants after bariatric surgery—What is the evidence?. J Thromb  Haemost 2022;20:1988
  10. Leven et al. Full-dose rivaroxaban in patients with a history of bariatric surgery: bridging the knowledge gap through a phase 1 study. J Thromb Haemost 2024;22:2844 (minimal alterations in drug pharmacokinetics after bariatric surgery)

Comparative studies – DOAC vs DOAC

  1.  Dawwas et al. Apixaban Versus Rivaroxaban in Patients With Atrial Fibrillation and Valvular Heart Disease. A Population-based study. Ann Intern Med 2022;175:1506  (Apixaban had better efficacy and safety than rivaroxaban)
  2. Lau et al. Comparative Effectiveness and Safety Between Apixaban, Dabigatran, Edoxaban, and Rivaroxaban Among Patients With Atrial Fibrillation. A Multinational Population-Based Cohort Study. Ann Intern Med 2022;175:1515 (Apixaban safer)
  3. Ingason et al. Comparison of the effectiveness and safety of direct oral anticoagulants: nationwide propensity score-weighted study. Blood Adv 2022; (Epub) (Apixaban causes less bleeding than rivaroxaban)
  4. Fralick et al. Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study. Ann Intern Med 2020;172:463 (Apixaban had better efficacy and safety in this large retrospective study)
  5. Hernandez et al. Comparison of the Effectiveness and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Newly Diagnosed Atrial Fibrillation. Am J Cardiol 2017;(epub) (Apixaban had most favorable safety/efficacy profile)
  6. Dawwas et al. Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation A Population-Based Cohort Study. Ann Intern Med 2021;174:910 (Apixaban had best safety and efficacy)
  7. Noseworthy et al. Direct Comparison of Dabigatran, Rivaroxaban, and Apixaban for Effectiveness and Safety in Nonvalvular Atrial Fibrillation. Chest 2016; 150:1302(The three drugs have similar efficacy; bleeding risk lowest with apixaban, highest with rivaroxaban)
  8. Graham et al. Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. JAMA Int Med 2016;176:1662(Relatively high risk of intra- and extracranial bleeding with rivaroxaban)
  9. Dawwas  and Cuker. Comparative effectiveness and safety of rivaroxaban with other oral anticoagulants in older adults with nonvalvular atrial fibrillation: Population-based analysis in response to updated Beers criteria. J Thromb Haemost 2024 (Epub) (More strokes and more bleeding with rivaroxaban compared to apixaban)
  10. Maura et al. Comparison of the Short-Term Risk of Bleeding and Arterial Thromboembolic Events in Nonvalvular Atrial Fibrillation Patients Newly Treated With Dabigatran or Rivaroxaban Versus Vitamin K Antagonists. A French Nationwide Propensity-Matched Cohort Study. Circulation 2015;132:1252(No significant differences in thromboembolic or bleeding rates between VKA and DOAC users)
  11. Li et al. Direct comparative effectiveness and safety between non-vitamin K antagonist oral anticoagulants for stroke prevention in nonvalvular atrial fibrillation: a systematic review and meta-analysis of observational studies. Eur J Epidemiol 2018 (Epub) (Apixaban, rivaroxaban and dabigatran have similar efficacy; apixaban has best safety profile)
  12. Ray et al. Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding. JAMA 2018;320:2221(Rivaroxaban associated with highest incidence of UGI bleeding, apixaban with lowest incidence; concomitant PPI therapy associated with lower incidence)
  13. Chan et al. Effectiveness and Safety of Four Direct Oral Anticoagulants in Asians with Non-valvular Atrial Fibrillation, Chest 2019 (Epub)(Edoxaban, apixaban and rivaroxaban gave lower risk of stroke or embolism than warfarin; edoxaban and apixaban had lowest bleed risk; retrospective study)
  14. Deitelzweig et al. Comparisons between Oral Anticoagulants among Older Nonvalvular Atrial Fibrillation Patients. J Am Geriatr Soc 2019 (Epub)(All DOACs gave lower risk or stroke/embolism than warfarin, apixaban had lowest rate of bleeding; retrospective study)
  15. Arval et al. Systematic review and meta-analysis of the efficacy and safety of apixaban compared to rivaroxaban in acute VTE in the real world. Blood Adv 2019;3:2381(Equivalent efficacy, bleeding rates lower with apixaban)
  16. Kjerpeseth et al. Comparative effectiveness of warfarin, dabigatran, rivaroxaban and apixaban in non-valvular atrial fibrillation: A nationwide pharmacoepidemiological study. PLOS One 2019;14:e0221500(Efficacy similar for all 4 drugs; less bleeding with dabigatran and apixaban)
  17. Jansson et al. Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and rivaroxaban in atrial fibrillation. Thromb Res 2019 (Epub).(Standard dose apixaban and dabigatran have lower bleed risk than rivaroxaban; low dose apixaban has lower risk than dabigatran or rivaroxaban. All had equal efficacy)
  18. López-López et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ 2017;359:j5058(Compares efficacy & safety of available anticoagulants in AF; apixaban had best outcomes, was cosf-effective vs warfarin)
  19. Deng et al. Efficacy and Safety of Direct Oral Anticoagulants in Elderly Patients With Atrial Fibrillation: A Network Meta-Analysis. Front Med (Lausanne) 2020;7:107(DOACs as a class superior to warfarin, apixaban superior to other DOACs)
  20. Durand et al. Effectiveness and Safety among Direct Oral Anticoagulants in Non Valvular Atrial Fibrillation: A Multi-Database Cohort Study with Meta-Analysis. Br J Clin Pharmacol 2020 (Epub)(Apixaban treatment led to feweer strokes and major bleeding episodes than rivaroxaban)
  21. Tobe et al. Comparison of Anti-factor Xa Activity Among Three Different Factor Xa Inhibitors in Non-valvular Atrial Fibrillation Patients With Renal Impairment. Clin Drug Investig 2020 (Epub)(Apixaban had lowest peak:trough ratio)
  22. Lip et al. Comparative safety and effectiveness of oral anticoagulants in key subgroups of patients with non-valvular atrial fibrillation and at high risk of gastrointestinal bleeding: A cohort study based on the French National Health Data System (SNDS). PLOS One 2025 (EPUB) (Apixaban safest)
  23. Cohen et al. Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis. PLoS One 2015;10:e0144856(DOACs have comparable efficacy for VTE, apixaban has best safety profile)
  24. Sindet-Pedersen et al. Safety and effectiveness of rivaroxaban and apixaban in patients with venous thromboembolism – a nationwide study. Eur Heart J Cardiovasc Pharmacother. 2018 (Epub)(No significant difference in mortality, VTE recurrence or bleeding)
  25. Dawwas et al. Effectiveness and safety of apixaban versus rivaroxaban for prevention of recurrent venous thromboembolism and adverse bleeding events in patients with venous thromboembolism: a retrospective population-based cohort analysis. Lancet Haematol 2019;6:e20(Lower recurrence rate and less bleeding with apixaban)
  26. Lutsey et al. Risk of hospitalised bleeding in comparisons of oral anticoagulant options for the primary treatment of venous thromboembolism. Br JHaematol 2019 (Epub)(Lower risk of bleeding requiring hospitalization with apixaban vs either rivaroxaban or warfarin in this retrospective analysis)
  27. Highcock et al. A Prospective Cohort Comparative Study of Rivaroxaban, Dabigatran, and Apixaban Oral Thromboprophylaxis in 2431 Hip and Knee Arthroplasty Patients: Primary Efficacy Outcomes and Safety Profile. J Arthroplasty 2020 (Epub)
  28. Kim et al. Frailty and Clinical Outcomes of Direct Oral Anticoagulants Versus Warfarin in Older Adults With Atrial Fibrillation. A Cohort Study. Ann Intern Med 2021;174:1214 (Apixaban safest in frail patients)
  29. Mamas et al. Meta-Analysis Comparing Apixaban Versus Rivaroxaban for Management of Patients With Nonvalvular Atrial Fibrillation. Am J Cardiol 2021 (Epub). (Apixaban causes less bleeding, no less effective than rivaroxaban)
  30. Ray et al. Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation. JAMA 2021326:2395 (More adverse events with rivaroxaban than with apixaban)
  31. Wang et al. Bleeding Risks With Non–Vitamin K Oral Anticoagulants Versus Single Antiplatelet Therapy: A Systematic Review and Meta-analysis of Randomized Trials. Ann Intern Med 2025 (Epub) (Major bleeding rates with apixaban & dabigatran similar to that with low dose ASA; rivaroxaban bleeding rates higher)
  32. Dawwas and Cuker. Comparative effectiveness and safety of rivaroxaban with other oral anticoagulants in older adults with nonvalvular atrial fibrillation: population-based analysis in response to updated Beers Criteria. J Thromb Haemost 2025;23:546 (Higher stroke and embolism rate with rivaroxaban than apixaban; more bleeding with rivaroxaban than warfarin, dabigatran or apixaban)

Safety & toxicity

  1. Abraham et al. Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study. Gastroenterol 2017;152:1014.(Lowest rates of GI bleeding with apixaban)
  2. Guo et al. Differences In Gastrointestinal Safety Profiles Among Novel Oral Anticoagulants: Evidence From A Network Meta-Analysis. Clin Epidemiol 2019 (Epub)(Apixaban and edoxaban gave lower GI bleed rates than rivaroxaban and dabigatran)
  3. Lega et al. Consistency of safety profile of new oral anticoagulants in patients with renal failure. J Thromb Haemost 2014;12:337 (Relative risk of bleeding vs warfarin not increased with GFR < 50)
  4. Beyer-Westendorf et al. Pregnancy outcome in patients exposed to direct oral anticoagulants – and the challenge of event reporting. Thromb Haemost 2016;116:651(Limited data shows a 2% risk of embryopathy from DOACs)
  5. Graham et al. Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. JAMA Int Med 2016 (Epub).(Bleeding risk and mortality with rivaroxaban higher than with dabigatran)
  6. Lip et al. Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin. A propensity score matched analysis. Thromb Haemost 2016;116:975(Apixaban and dabigatran users had lowest bleed risk)
  7. Siegal et al. How I treat target-specific oral anticoagulant-associated bleeding. Blood 2014;123:1152
  8. Harel et al. Comparisons between novel oral anticoagulants and vitamin K antagonists in patients with CKD. J Am Soc Nephrol 2014 (ePub)(No difference in efficacy or safety between NOACs and VKAs in patients with CrCl 30-50)
  9. Raccah et al. Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest 2016 (Epub) (Apixaban less likely to cause bleeding in patients with decreased kidney function)
  10. Ha et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019;171:181(DOACs had better benefit/risk ratio than warfarin in early stage CKD)
  11. Steinberg et al. Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes : The ORBIT-AF II Registry. J Am Coll Cardiol 2016;24:2597(Off label dosing markedly increases complication rates)
  12. Perzborn et al. Direct thrombin inhibitors, but not the direct factor Xa inhibitor rivaroxaban, increase tissue factor-induced hypercoagulability in vitro and in vivo. J Thrombo Haemost 2014;12:1054
  13. Liakoni et al. Hepatotoxicity of new oral anticoagulants (NOACs). Drug Saf 2015 (Epub)
  14. Lameijer et al. Efficacy and safety of direct oral anticoagulants during pregnancy; a systematic literature review. Thromb Res 2018;169:123
  15. Quinn et al. Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial. J Am Heart Assoc 2018;7:e008755(No significant increase in bleeding risk when SSRI used together with DOAC; minimal increase in risk with SSR+warfarin)
  16. Vasquez S. Drug-drug interactions in an era of multiple anticoagulants: a focus on clinically relevant drug interactions. Blood 2018;132:2230
  17. Hill et al. Risk of Hospitalization With Hemorrhage Among Older Adults Taking Clarithromycin vs Azithromycin and Direct Oral Anticoagulants. JAMA Intern Med 2020;180:1052 (Bleeding risk higher with clarithromycin)
  18. Ray et al. Risk for Bleeding-Related Hospitalizations During Use of Amiodarone With Apixaban or Rivaroxaban in Patients With Atrial Fibrillation. A Retrospective Cohort Study. Ann Intern Med 2023;176:769 (Concomitant amiodarone use increases bleeding risk)
  19. Ray et al. Serious Bleeding in Patients With Atrial Fibrillation Using Diltiazem With Apixaban or Rivaroxaban. JAMA 2024 (Epub)
  20. Huisman et al. Less abnormal uterine bleeding with dabigatran than warfarin in women treated for acute venous thromboembolism. J Thromb Haemost 2018;16:1775
  21. Chang et al. Association Between Use of Non–Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation. JAMA 2017;318:1250 (Concurrent use of amiodarone, fluconazole, rifampin and phenytoin increased risk of major bleeding with DOACs)
  22. Zhang et al. Risk of major bleeding among users of direct oral anticoagulants combined with interacting drugs: a population-based nested case-control study. Br J Clin Pharmacol 2020 (Epub)(Antiplatelet drugs and SSRIs increased bleeding risk)
  23. Souverein et al. Comparing risk of major bleeding between users of different oral anticoagulants in patients with nonvalvular atrial fibrillation. Br J Clin Pharmacol 2020 (Epub)(Bleeding risk lower with apixaban than dabigatran or rivaroxaban)
  24. Xu et al. Direct Oral Anticoagulant- or Warfarin-Related Major Bleeding. Chest 2017;152:81(Lower mortality with bleeding on DOACs than on warfarin, despite high rates of warfarin reversal)
  25. Wang et al. Bleeding Risk in Nonvalvular Atrial Fibrillation Patients Receiving Direct Oral Anticoagulants and Warfarin: A Systematic Review and Meta-Analysis of Observational Studies. TH Open 2020;4:e145(Apixaban and dabigatran, but not rivaroxaban, have lower bleed risk than VKAs)
  26. Inohara et al. Association of Intracerebral Hemorrhage Among Patients Taking Non–Vitamin K Antagonist vs Vitamin K Antagonist Oral Anticoagulants With In-Hospital Mortality. JAMA 2018;319:463(Lower in-hospital mortality in DOAC users with ICH vs warfarin)
  27. Wolfe et al. A systematic review and Bayesian network meta‐analysis of risk of intracranial hemorrhage with direct oral anticoagulants. J Thromb Haemost 2018;16:1296(Dabigatran 110 mg bid safest, rivaroxaban least safe)
  28. Holster et al. New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding: A Systematic Review and Meta-analysis. Gastroenterology 2013;146:106
  29. Hernandez et al. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Int Med 2015;175:18 (Higher overall bleeding risk with dabigatran than warfarin, particularly GI bleeding, in this post-approval data analysis)
  30. Aggarwal et al. Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants. Circulation 2023;148:936
  31. Bai et al. Associations of acute kidney injury with oral anticoagulants: a disproportionality analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Expert Opin Drug Saf 2025 (Epub) (Apixaban less likely to be associated with AKI than other DOACs)

Laboratory testing

  1. Connors JM. Testing and monitoring direct oral anticoagulants. Blood 2018;132:2009
  2. Samuelson et al. Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants. A Systematic Review. Chest 2017;151:127
  3. Bernier et al. Therapeutic Drug Monitoring of Direct Oral Anticoagulants May Increase Their Benefit-Risk Ratio. J Cardiovasc Pharmacol 2020;76:472
  4. Yin et al. Linking Endogenous Factor Xa Activity, a Biologically Relevant Pharmacodynamic Marker, to Edoxaban Plasma Concentrations and Clinical Outcomes in the ENGAGE AF-TIMI 48 Trial. 2018; 138:1963
  5. Gosselin and Adcock. The laboratory’s 2015 perspective on direct oral anticoagulant testing. J Thromb Haemost 2016;14:886
  6. Gladstone et al. How to Monitor Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Practice Tool Endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society. Ann Intern Med 2015;163:382
  7. Tripodi A. The laboratory and the direct oral anticoagulants. Blood 2013;121:4032
  8. Garcia et al. Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemost 2013; 11:245
  9. Kim et al. Mechanistic Basis for the Differential Effects of Rivaroxaban and Apixaban on Global Tests of Coagulation. TH Open 2018;2:e190

Pregnancy & lacctation

  1. Daei et al. Direct oral anticoagulant safety during breastfeeding: a narrative review. Eur J Clin Pharmacol 2021 (Epub)(Dabigatran has least excretion into breast milk, apixaban the most)
  2. Beyer-Westendorf et al. Safety of direct oral anticoagulant exposure during pregnancy: a retrospective cohort study. Lancet Haematol 2020;7:e884
  3. Wiesen et al. The direct factor Xa inhibitor rivaroxaban passes into human breast milk. Chest 2016;150:e1
  4. Zhao et al. Are apixaban and rivaroxaban distributed into human breast milk to clinically relevant concentrations? Blood 2020;136:1783(More apixaban gets into breast milk than rivaroxaban)
  5. Sessa et al. Direct-acting oral anticoagulants (DOACs) in pregnancy: new insight from VigiBase®. Sci Rep 2019;9:7236

Rivaroxaban

  1. Eriksson et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty. NEJM 2008; 358:2765(“major” VTE rate 0.2% with rivaroxaban, 2% with enoxaparin; no significant difference in bleeding rate)
  2. Lassen et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Total Knee Arthroplasty. NEJM 2008;358:2776(“major” VTE rate 1% with rivaroxaban, 2.6% with enoxaparin; bleeding rates similar)
  3. Anderson et al. Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. NEJM 2018;378:699(Rivaroxaban x 5 days followed by ASA alone gave equivalent outcomes to extended rivaroxaban treatment)
  4. Samama et al Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery. NEJM 2020;382:1916(PRONOMOS study; major VTE in 0.2% of rivaroxaban cohort vs 1.1% with enoxaparin; bleeding risk not different)
  5. Lazo-Langer et al. Rivaroxaban vs. low molecular weight heparin for the prevention of venous thromboembolism after hip or knee arthroplasty: a cohort study. J Thromb Haemost 2014;12:1626(RR of VTE 40% lower with rivaroxaban, no difference in bleeding rates)
  6. Camporese et al. Efficacy of Rivaroxaban for thromboprophylaxis after Knee Arthroscopy (ERIKA). A phase II, multicentre, double-blind, placebo-controlled randomised study. Thromb Haemost 2016;116:205(10 mg/d of rivaroxaban x 7 days superior to placebo in this small study)
  7. Cohen et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. NEJM 2013;368:513(Slightly lower VTE rate with rivaroxaban 10 mg/day x 35 days vs enoxaparin 40 mg/day x 10 days; more bleeding with rivaroxaban)
  8. Cohoon et al. Rivaroxaban for thromboprophylaxis among patients recently hospitalized for acute infectious diseases: a subgroup analysis of the MAGELLAN study. J Thromb Haemost 2018;16:1278(Less VTE, more bleeding with rivaroxaban 10 mg/day x 35 days vs enoxaparin 40 mg/day x 10 days)
  9. Spyropoulos et al. Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness. NEJM 2018;379:1118(MARINER trial; non-significant reduction in VTE rate with 45 day course of low dose rivaroxaban, little bleeding)
  10. Spyropolous et al. Post-Discharge Prophylaxis With Rivaroxaban Reduces Fatal and Major Thromboembolic Events in Medically Ill Patients. J Am Coll Cardiol 2020;75:3140(Re-analysi of MARINER trial including both arterial & venous events; 28% reduction in major thromboembolism using rivaroxaban 10 mg/d, no increase in bleeding)
  11. Spyropolous et al. Association of Bleeding Severity With Mortality in Extended Thromboprophylaxis of Medically Ill Patients in the MAGELLAN and MARINER Trials. Circulation 2022;145:1471
  12. Khorana et al. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. NEJM 2019;380:720(Rivaroxaban lowered VTE rate from 6.4% to 2.6% while patients on treatment, but over 40% discontinued treatment. Major bleeding 2% with rivaroxaban vs 1% with placebo; with editorial)
  13. Buller et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein–DVT Dose-Ranging Study. Blood 2008;112:2242
  14. Nisio et al. Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies. Thromb Haemost 2016;116:739(Standard dose of rivaroxaban safe & effective in patients with weights between 50-140 kg)
  15. EINSTEIN investigators. Oral rivaroxaban for symptomatic venous thromboembolism. NEJM 2010;363:2499(Rivaroxaban as effective and safe as warfarin after acute DVT. Extended treatment with rivaroxaban safe & effective)
  16. EINSTEIN-PE investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. NEJM 2012;366:1287(Rivaroxaban noninferior to standard therapy)
  17. Prins et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013;11:21
  18. Wells et al. Long-term anticoagulation with rivaroxaban for preventing recurrent VTE: A benefit–risk analysis of EINSTEIN EXTENSION. Chest 2016 (Epub)(Rivaroxaban reduced VTE incidence from 9.6% to 3% in one year; 0.7% incidence of major bleeding)
  19. Weitz et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. NEJM 2017;376:1211(Recurrent VTE incidence reduced by 75% with 10 mg/day rivaroxaban, major bleeding rate 0.4%/yr vs 0.3% with ASA; with editorial)
  20. Larsen et al. Effectiveness and safety of rivaroxaban and warfarin in patients with unprovoked venous thromboembolism: a propensity-matched nationwide cohort study. Lancet Haematol 2017;4:e237(Rivaroxaban reduced recurrence rate by 25% vs warfarin, with a slight increase in bleeding risk)
  21. Soares et al. Comparison of the recanalization rate and postthrombotic syndrome in patients with deep venous thrombosis treated with rivaroxaban or warfarin. Surgery 2019 (Epub). (Postthrombotic syndrome in 29% of warfarin treated patients vs 9% of rivaroxaban treated patients after 1 year in this small randomized trial)
  22. Male et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol 2019 (Epub)(Weight-adjusted rivaroxaban treatment associated with lower resdual clot burden vs standard anticoagulation, similar safety)
  23. Patel et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. NEJM 2011;365:883(Rivaroxaban non-inferior to warfarin)
  24. Guimarães et al. Rivaroxaban in Patients with Atrial Fibrillation and a Bioprosthetic Mitral Valve. NEJM 2020;383:2117(HR for stroke 0.25 with riv vs warfarin, no increase in bleeding risk)
  25. Mahaffey et al. End of Study Transition From Study Drug to Open-Label Vitamin K Antagonist Therapy: The ROCKET AF Experience. Circ Cardiovasc Qual Outomes 2013;6:470(Excess strokes following withdrawal of rivaroxaban likely due to poor INR control during transition to warfarin)
  26. Hart et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. NEJM 2018;378:2191 (Rivaroxaban 15 mg daily not superior to ASA 100 mg/day, caused more bleeding)
  27. Mega et al. Rivaroxaban in patients with a recent acute coronary syndrome. NEJM 2012;366:9(Rivaroxaban reduced risk of death from cardiovascular events, with some increased risk of major bleeding)
  28. Eikelboom et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. NEJM 2017;377:1319(Rivaroxaban 2.5 mg bid +ASA had better cardiac outcomes but more bleeding than ASA alone; with editorial)
  29. Yasuda et al. Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease. NEJM 2019 (Epub)(Rivaroxaban 10-15 mg/d as effective as R + antiplatelet drug, caused less bleeding; with editorial)
  30. Branch et al. Rivaroxaban With or Without Aspirin in Patients With Heart Failure and Chronic Coronary or Peripheral Artery Disease. The COMPASS Trial. Circulation 2019;140:529 (Benefit of adding low dose rivaroxaban to ASA greater in patients with heart failure)
  31. Connolly et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:205(COMPASS-1 trial; Adding rivaroxaban to antiplatelet therapy lowered major vascular events but increased major bleeding; deaths reduced by 23%)
  32. Anand et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2017;31:219(COMPASS-2 trial; Rivaroxaban + ASA reduced major adverse CV events vs ASA alone, with more major bleeding)
  33. Eikelboom et al. Mortality Benefit of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary or Peripheral Artery Disease. J Am Coll Cardiol 2021;78:14 (COMPASS trial)
  34. Bonaca et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. NEJM 2020;382:1994 (Rivaroxaban 2.5 mg bid modestly reduced incidence of vascular events vs ASA, no difference in bleeding)
  35. Bhatt et al. The Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes and Cardiovascular Disease: Insights from the COMPASS Trial. Circulation 2020;141:1841 (Relative benefit of adding rivaroxaban to ASA greater in diabetic patients)
  36. Bainey et al. Rivaroxaban Plus Aspirin Versus Aspirin Alone in Patients With Prior Percutaneous Coronary Intervention (COMPASS-PCI). Circulation 2020;141:1141 (Riv +ASA reduced mortality vs ASA, with increased bleed risk)
  37. Stffel et al. The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared With Aspirin in Patients With Chronic Vascular Disease. Circulation 2020;142:40
  38. Pogosova et al. Rivaroxaban 2.5 mg Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients With Chronic Atherosclerosis. Circulation 2022;145:1875
  39. Bauersachs et al. Total Ischemic Event Reduction with Rivaroxaban after Peripheral Arterial Revascularization in the VOYAGER PAD Trial. J Am Coll Cardiol 2021 (Epub)
  40. Debus et al. Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial. Circulation 2021;144:1104
  41. Ramaciotti et al. Rivaroxaban for Patients with Intermittent Claudication. NEJM Evid 2024 (Epub)
  42. Ohman et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet 2017;389:1799(Rivaroxaban 2.5 mg bid did not cause more bleeding than ASA when combined with a P2Y12 inhibitor)
  43. Zannad et al. Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease. NEJM 2018;379:1332(Rivaroxaban 2.5 mg bid did not lower combined risk of death, MI, stroke; no reduction in mortality)
  44. Mehra et al. A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial. Eur Heart J 2019 (Epub)(Post hoc analysis of above trial showing modest reduction in stroke risk with rivaroxaban)
  45. Mahaffey et al. Clinical Outcomes With Rivaroxaban in Patients Transitioned From Vitamin K Antagonist Therapy: A Subgroup Analysis of a Randomized Trial. Ann Intern Med 2013;158:861
  46. Wasserlauf et al. Meta-analysis of rivaroxaban and bleeding risk. Am J Cardiol 2013;112:454(Less fatal bleeding, no significant difference in overall mortality vs VKA)
  47. Ageno et al. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol 2016;3:e12(Rivaroxaban-treated patients generally younger, healthier; they had less recurrent VTE and lower mortality)
  48. Piccini et al Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation. Circulation 2016;133:352(Polypharmacy associated with higher bleed risk)
  49. Gibson et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. NEJM 2016;375:2423 (Low dose rivaroxaban plus antiplatelet therapy caused less bleeding than warfarin plus antiplatelet therapy)
  50. Brunner-Ziegler et al. Comparison between the impact of morning and evening doses of rivaroxaban on the circadian endogenous coagulation rhythm in healthy subjects. J Thromb Haemost 2016;14:316(Evening dosing may be preferable)
  51. Wiesen et al. The direct factor Xa inhibitor rivaroxaban passes into human breast milk. Chest 2016;150:e1
  52. Zhao et al. Are apixaban and rivaroxaban distributed into human breast milk to clinically relevant concentrations? Blood 2020;136:1783(More apixaban gets into breast milk than rivaroxaban)
  53. Weisen et al. Residual rivaroxaban exposure after discontinuation of anticoagulant therapy in patients undergoing cardiac catheterization. Eur J Clin Pharmacol 2018 (Epub)(Stopping 48 hours prior to procedure results in safe blood levels for most patients)
  54. Coleman et al. Effectiveness and Safety of Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation Patients with Severe Kidney Disease or Undergoing Hemodialysis. Am J Med 2019 (Epub)(Less bleeding with rivaroxaban, similar efficacy)
  55. Alberts et al. Risks of Stroke and Mortality in Atrial Fibrillation Patients Treated With Rivaroxaban and Warfarin. Stroke 2019 (Epub) (19% risk reduction for stroke, lower stroke severity and mortality with rivaroxaban in this retrospective study sponsored by drug maker)
  56. Weir et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and stage IV-V chronic kidney disease. Am Heart J 2020;223:3(Rivaroxaban as safe as warfarin)
  57. Shyamkumar et al. Plasma Rivaroxaban Level to Identify Patients at Risk of Drug Overexposure: Is a Single Measurement of Drug Level Reliable? TH Open 2021;5:e84(Less than 30% of patients with high blood levels had high levels 2 mo later)

Apixaban

  1. Lassen et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. NEJM 2009;361:594
  2. Lassen et al. Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement. NEJM 2010;363:2487(Apixiban group had less VTE, no increase in bleeding)
  3. Connolly et al. Apixaban in patients with atrial fibrillation. NEJM 2011;364:806(The “AVERROES” trial; `Apixaban better than aspirin in patients for whom warfarin treatment deemed “unsuitable”)
  4. Buckley et al. Effectiveness and Safety of Apixaban in over 3.9 Million People with Atrial Fibrillation: A Systematic Review and Meta-Analysis. J Clin Med 2022;11:3788 (Apixaban has “better overall safety and efficacy profile compasred to VKAs and other DOACs”)
  5. Granger et al. Apixaban versus warfarin in patients with atrial fibrillation. NEJM 2011;365:981(Apixaban more effective and safer than warfarin, associated with slightly lower mortality; with editorial)
  6. Lopes et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet 2012;380:1749(Outcomes with apixaban superior to those with warfarin regardless of CHADS score or bleeding risk)
  7. Avezum et al. Apixaban compared with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the ARISTOTLE trial. Circulation 2015;132:624(> 25% of patients in this trial had significant valvular disease; relative benefit of apixaban in this group no different from that in overall trial)
  8. Wallentin et al. Efficacy and Safety of Apixaban Compared With Warfarin at Different Levels of Predicted International Normalized Ratio Control for Stroke Prevention in Atrial Fibrillation. Circulation 2013;127:2166(Patients predicted to have worse INR control on warfarin had greater benefit from apixaban)
  9. Alexander et al. Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome. NEJM 2011;365:699(Apixaban increased bleeding, did not reduce ischemic events significantly)
  10. Garcia et al. Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures. Blood 2014;124:3692(Short term interruption of treatment safe; some patients may not need to stop Rx)
  11. Komócsi et al. Use of New-Generation Oral Anticoagulant Agents in Patients Receiving Antiplatelet Therapy After an Acute Coronary Syndrome: Systematic Review and Meta-analysis of Randomized Controlled Trials. Arch Intern Med 2012;172:1537(Combined use of new anticoagulants + antiplatelet therapy associated with dramatic increase in major bleeding)
  12. Goldhaber et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. NEJM 2011;365:2167(Extended thromboprophylaxis with apixaban not superior to a shorter course of enoxaparin, caused more bleeding)
  13. Carrier et al. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. NEJM 2019;380:711(Apixaban lowered VTE rate from 10.2% to 4.2%, increased major bleeding rate from 1.1% to 2.2%; with editorial)
  14. Agnelli et al. Oral apixaban for the treatment of acute venous thromboembolism. NEJM 2013;369:799(The AMPLIFY trial; Apixaban as effective as standard treatment, caused less bleeding)
  15. Agnelli et al. Apixaban for extended treatment of venous thromboembolism. NEJM 2013;368:699(Apixaban lowered VTE recurrence rate from 8.8% to 1.7% over 12 mo without increasing bleeding risk; with editorial)
  16. Weyker et al. Bleeding and recurrent VTE with apixaban vs warfarin as outpatient treatment: time-course and subgroup analyses. Blood Adv 2020;4:432(Apixaban causes less bleeding and is more effective in preventing recurrent VTE than LMWH/warfarin)
  17. Pathak et al. Meta-Analysis on Risk of Bleeding With Apixaban in Patients With Renal Impairment. Am J Cardiol 2015;115:323(Apixaban is as safe or safer than “conventional agents” in patients with mild or moderate renal impairment)
  18. Chang et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol 2015;56:637(“These results suggest that dose adjustment of apixaban is not required on the basis of renal function alone”)
  19. Raccah et al. Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest 2016;149:1516 (Apixaban less likely to cause bleeding in patients with decreased kidney function)
  20. Siontis et al. Outcomes Associated with Apixaban Use in End-Stage Kidney Disease Patients with Atrial Fibrillation in the United States. Circulation 2018 (Epub)(5 mg bid dose associated with lower risk of embolic compicatons and death than 2.5 mg bid dose or warfarin)
  21. Stanifer et al. Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease. Circulation 2020;141:1384 (Apixaban 5 mg bid safer than warfarin for patients with GFR 25-30 mL/min)
  22. Hanni et al. Outcomes associated with apixaban vs warfarin in patients with renal dysfunction. Blood Adv 2020;4:2366(Retrospective study. Apixaban appears superior to warfarin in patients with CrCl < 25)
  23. Garza-Mayers et al. The Successful Use of Apixaban in Dialysis Patients with Calciphylaxis Who Require Anticoagulation: A Retrospective Analysis. Am J Nephrol 2018;48:168
  24. Caraballo et al. Compounded Apixaban Suspensions for Enteral Feeding Tubes. Hosp Pharm 2017;52:478
  25. Honloser et al. Efficacy and Safety of Apixaban versus Warfarin in Patients with Atrial Fibrillation and Extremes in Body Weight: Insights from the ARISTOTLE Trial. Circulation 2019; 139:2292 (Outcomes with apixaban superior to those with warfarin in all weight groups)
  26. Lopes et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. NEJM 2019;380:1509(AUGUSTUS trial: Apixaban + P2Y12 inhibitor superior to VKA + P2Y12 inhibitor; no clear benefit from addidntgASA. With editorial )
  27. Alexander et al. The Risk / Benefit Tradeoff of Antithrombotic Therapy in Patients with Atrial Fibrillation Early and Late After an Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights from AUGUSTUS. Circulation 2020 (Epub)(Benefit of adding ASA to DOAC reduces ischemic events; after 30 days this benefit disappears, but bleeding risk remains higher with ASA + Riv)
  28. Lutsey et al. Association of Anticoagulant Therapy With Risk of Fracture Among Patients With Atrial Fibrillation. JAMA Intern Med 2019 (Epub). (Fracture risk lowest withy apixaban)
  29. Zhao et al. Are apixaban and rivaroxaban distributed into human breast milk to clinically relevant concentrations? Blood 2020;136:1783(More apixaban gets into breast milk than rivaroxaban)
  30. Milner et al. Assessment of Anti-Xa activity in patients receiving concomitant apixaban with strong p-glycoprotein inhibitors and statins. J Clin Pharm Ther 2022 (Epub)

Edoxaban

  1. Edoxaban (Savasaya) – the fourth new oral anticoagulant. JAMA 2015;314:76
  2. Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. NEJM 2013;369:1406 (Similar efficacy, less bleeding with edoxaban)
  3. Agnelli et al. Treatment of Venous Thromboembolism with Edoxaban over 18 Months: Results from ETNA-VTE Europe. Thromb Haemost 2025 (Epub) (“Real-world” outcomes similar to those in above clinical trial)
  4. Giugliano et al. Edoxaban versus warfarin in patients with atrial fibrillation. NEJM 2013;369:2093(Similar efficacy, less bleeding and lower cardiovascular mortality with edoxaban)
  5. Bergmark et al. Comparison of Events Across Bleeding Scales in the ENGAGE AF-TIMI 48 Trial. Circulation 2019 (Epub)
  6. Vranxkx et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet 2019;394:1335
  7. Brekelmans et al. Recurrent venous thromboembolism in patients with pulmonary embolism and right ventricular dysfunction: a post-hoc analysis of the Hokusai-VTE study. Lancet Haematol 2016;3:e437 (Edoxaban more effective than warfarin for treating and preventing recurrence of PE with RV dysfunction)
  8. Raskob et al. Extended duration of anticoagulation with edoxaban in patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE study. Lancet Haematol 2016;3:e228(Edoxaban as effective as warfarin, caused less bleeding)
  9. Ruff et al. Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015;385:2288(Adjusting dose based on clinical factors preserves effficacy and lowers bleeding risk in patients with AF)
  10. Mega et al. Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015; 385: 2280(CYP2C9 and VKORC genotyopes associated with greater warfarin sensitivity and higher bleeding risk with warfarin treatment; safety advantage with edoxaban is greater in such patients)
  11. Boriani et al. Relationship between body mass index and outcomes in patients with atrial fibrillation treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial. Eur Heart J 2019 (Epub)(Efficacy and safety of edoxaban did not vary across BMI categories from 18.5 to >40)
  12. Okumura et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. NEJM 2020;383:1735(15 mg/d of edoxaban superior to placebo, 3.3% annualized bleed rate in Japanese pts >80 yo)
  13. Bergmark et al. Comparison of Events Across Bleeding Scales in the ENGAGE AF-TIMI 48 Trial. Circulation 2019;140:1792(Bleeding risk lower with edoxaban – with editorial)
  14. Okumura et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. NEJM 2020;383:1735(Edoxaban 15 mg/day superior to placebo in preventing stroke/embolism without causing much more bleeding)
  15. Zelniker et al. Comparison of the Efficacy and Safety Outcomes of Edoxaban in 8040 Women Versus 13 065 Men With Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial. Circulation 2021;143:673(60 mg daily dose caused less major bleeding in women than men, and was equally effective in preventing stroke)
  16. Van Mieghem et al. Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR. NEJM 2021;385:2150(Edoxaban non-inferior but caused more GI bleeding)

Betrixaban

  1. Huisman and Klok. Pharmacological properties of betrixaban. Eur Heart J Suppl 2018:20 (Suppl E): E12-15
  2. Cohen et al. Extended thrombophrophylaxis with Betrixaban in acutely ill medical patients. NEJM 2016;375:534(Comparable efficacy and safety to LMWH)
  3. Gibson et al. Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients An APEX Trial Substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Circulation 2017;135:648
  4. Ageno et al. Net‐clinical benefit of extended prophylaxis of venous thromboembolism with betrixaban in medically ill patients aged 80 or more. J Thromb Haemost 2019;17:2089

Dabigatran

  1. Hawes et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013;11:1493(PT/INR and PTT often normal at therapeutic dabigatran levels)
  2. Chan et a. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost 2015;13:353(Considerable variation in blood levels between patients associated with age, weight, renal function)
  3. Eriksson et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178(Dabigatran as effective and safe as enoxaparin)
  4. Connolly et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. NEJM 2009;361:1139(Dabigatran as efficacious as warfarin, caused less bleeding. See also the accompanying editorial)
  5. Go et al. Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice: A Retrospective Cohort Study. Ann Intern Med 2017;167:845(Large retrospective study – dabigatran use associated with comparable rates of stroke and extracranial bleeding, less ICH, higher MI rate than warfarin)
  6. Mazurek et al. Safety and effectiveness of dabigatran at 2 years: Final outcomes from Phase II of the GLORIA-AF registry program. Am Heart J 2019;218:123(In 4873 AF patients the incidence per 100 person-years was 0.65 for stroke, 0.5 for MI, and 0.97 for major bleeding)
  7. Eikelboom et al. Dabigatran versus warfarin in patients with mechanical heart valves. NEJM 2013;369:1206(Dabigatran treatment associated with more thrombosis and more bleeding; see also letters to the editor)
  8. Andreas et al. Increased Thromboembolic Events With Dabigatran Compared With Vitamin K Antagonism in Left Ventricular Assist Device Patients A Randomized Controlled Pilot Trial. Circ Heart Fail 2017;10:e003709
  9. Eikelboom et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation. An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation 2011;123:2363(Overall bleeding risk with dabigatran relative to warfarin rises above age 75)
  10. Connolly et al. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation 2013;126:237(More bleeding with 150 mg bid than 110 mg bid, no reduction in stroke risk)
  11. Hernandez et al. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med 2015;175:18(Higher risk of non-CNS bleeding vs warfarin in this “real-world” study, especially in African-Americans and patients with CKD)
  12. Lau et al. Bleeding-related hospital admissions and 30-day readmissions in patients with non-valvular atrial fibrillation treated with dabigatran versus warfarin. J Thromb Haemost 2017;15:1923(More readmits for bleeding with dabigatran, higher incidence of GI bleeding)
  13. Hijazi et al. Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation. A RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) Trial Analysis. Circulation 2014;129:961(GFR <80 associated with higher bleeding rates)
  14. Healey et al. Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial. Circulation 2012;126:343(Bleeding rates similar for warfarin & dabigatran)
  15. Diener et al. Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source. NEJM 2019;380:1906(Dabigatran no more effective than ASA, caused more bleeding)
  16. Schulman et al. Perioperative Management of Dabigatran. A Prospective Cohort Study. Circulation 2015;132:167
  17. Dans et al. Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Trial. Circulation 2013;127:634(More bleeding with concomitant antiplatelet Rx, which did not affect the advantages of dabigatran vs warfarin)
  18. Schulman et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. NEJM 2009;361:2342(Efficacy and safety of fixed-dose dabigatran comparable to warfarin)
  19. Schulman et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. NEJM 2013;368:709(Dabigatran effective for extended Rx of VTE, less bleeding than with warfarin but more than with placebo; with editorial)
  20. Schulman et al. Treatment of Acute Venous Thromboembolism With Dabigatran or Warfarin and Pooled Analysis. Circulation 2014;129:764(Similar rates of recurrence and lower bleeding rate – 1.2% vs 1.7% – with dabigatran)
  21. Goldhaber et al. Treatment of acute pulmonary embolism with dabigatran versus warfarin A pooled analysis of data from RE-COVER and RE-COVER II. Thromb Haemost 2016;116:714 (Dabigatran as effective as warfarin, associated with 40% less bleeding)
  22. Uchino and Hernandez. Dabigatran association with higher risk of acute coronary events. Meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012;172:397(1.3-fold increase in risk of MI or ACI with dabigatran)
  23. Wei et al. Increased risk of myocardial infarction with dabigatran etexilate: fact or fiction? A critical meta-analysis of over 580,000 patients from integrating randomized controlled trials and real-world studies. Int J Cardiol 2018 (Epub) (No association found between dabigatran use and MI)
  24. Shah and Gage. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation 2011;123:2562(Dabigatran more cost-effective in patients at high risk of stroke or hemorrhage unless INR control with warfarin excellent)
  25. Pham et al. Association of Oral Anticoagulants and Verapamil or Diltiazem With Adverse Bleeding Events in Patients With Nonvalvular Atrial Fibrillation and Normal Kidney Function. JAMA Netw Open 2020; 3:e203593(Concomitant use of dabigatran with verapamil or diltiazem increased bleeding risk)
  26. Halton et al. Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics, safety, and tolerability. J Thromb Haemost 2017;15:2147(Dabigatran was relatively safe and effective in children with VTE; weight-based dosing)
  27. Devereaux et al. Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Lancet 2018; 391:2325(Dabigatran 110 mg bid reduced rate of vascular complications from 15% to 11%, no increase in bleeeding)
  28. Gaubert et al. Dabigatran versus vitamin k antagonist: an observational across‐cohort comparison in acute coronary syndrome patients with atrial fibrillation. J Thromb Haemost 2018;16:465(Dabigatran + antiplatelet therapy associated with higher thrombotic risk than VKA + antiplatelet therapy)
  29. Glund et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015;113:911
  30. Pollack et al. Idarucizumab for Dabigatran Reversal. NEJM 2015;373:511(With editorial)
  31. Pollack et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. NEJM 2017;377:431(All patients had 100% reversal of anticoagulant effect on clotting times; a few patients had rebound anticoag effect requiring another dose after 12-24h)
  32. Van Der Waal et al. Idarucizumab for Dabigatran Reversal in the Management of Patients With Gastrointestinal Bleeding. Circulation 2019;139:748 (98% had complete hemostatic reversal; 69% stopped bleeding within 24 h, 4.4% had thrombosis, 15% died. With editorial)
  33. Arellano-Rodrigo et al. Idarucizumab, but not procoagulant concentrates, fully restores dabigatran‐altered platelet and fibrin components of hemostasis. Transfusion 2019 (Epub)(in vitro data only)
  34. Kerner et al. Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany-Updated series of 120 cases. Int J Stroke 2020 (Epub)

Factor XI inhibitors

  1. Greco et al. Pharmacology and Clinical Development of Factor XI Inhibitors. Circulation 2023;14;897
  2. Gailani and Gruber. Targeting factor XI and factor XIa to prevent thrombosis. Blood 2024;143:1465
  3. Büller et al. Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. NEJM 2015;372:232(Less thrombosis and less bleeding with this drug than with enoxaparin in patients undergoing knee replacement; see editorial)
  4. Verhamme et al. Abelacimab for Prevention of Venous Thromboembolism. NEJM 2021;385:609(Anti-XI monoclonal Ab more effective than enoxaparin in preventing VTE after TKA)
  5. Thomas et al. First evaluation of the safety, pharmacokinetics, and pharmacodynamics of BAY 2433334, a small molecule targeting coagulation factor XIa. J Thromb Haemost 2021;19:2407
  6. Nowotny et al. First randomized evaluation of safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, an antibody targeting coagulation factor XI and factor XIa, in healthy men. J Thromb Haemost 2022;20:1684 (Can be given IV or SC; duration of effect almost 2 mo)
  7. Weitz et al. Milvexian for the Prevention of Venous Thromboembolism. NEJM 2021;385:2161(oral FXI inhibitor effective with low bleeding risk)
  8. Piccini et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet 2022;399:1383
  9. Ruff et al. Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation. NEJM 2025;392:361 (Trend toward more strokes, but less bleeding with abelacimab; with editorial)
  10. Shoamanesh et al. Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet 2022;400:997 (No increase in bleeding but no apparent benefit)
  11. Piccini et al. Asundexian versus Apixaban in Patients with Atrial Fibrillation. NEJM 2025;392:23 (Higher incidence of stroke/embolism with asundexian with somewhat lower bleed risk)
  12. Ruff et al. Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation. NEJM 2025;392:361 (MoAb to XI caused less bleeding than rivaroxaban, with a trend toward higher stroke rates; with editorial)
  13. Weitz et al. Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty. The FOXTROT Randomized Clinical Trial. JAMA 2020;323:130(Anti- XIa antibody given prior to surgery had efficacy superior to enoxaparin; efficacy similar to apixaban but with more bleeding)
  14. Weitz et al. Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial. Nat Med 2024;30:435
  15. Presume et al. Achieving higher efficacy without compromising safety with factor XI inhibitors versus low molecular weight heparin for the prevention of venous thromboembolism in major orthopedic surgery—Systematic review and meta-analysis. J Thromb Haemost 2022;20:2930

Other/investigational agents

  1. Weitz and Chan. Novel antithrombotic strategies for treatment of venous thromboembolism. Blood 2020;135:351
  2. Travers et al. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood 2014;124:3183(In mice)
  3. Lorentz et al. The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial. Blood 2021;138:2173
  4. Andreozzi et al. Sulodexide for the Prevention of Recurrent Venous Thromboembolism. The Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. Circulation 2015;132:1891(Drug reduced VTE recurrence rate by 50% with no apparent increase in bleed risk)
  5. Carroll et al. Sulodexide in venous disease. J Thromb Haemost 2019;17:3
  6. Fredenburgh et al. Emerging anticoagulant strategies. Blood 2017;129:147
  7. Plow et al. The search for new antithrombotic mechanisms and therapies that may spare hemostasis. Blood 2017;131:1899

Thrombolytic treatment

  1. Perlroth et al. Effectiveness and Cost-effectiveness of Thrombolysis in Submassive Pulmonary Embolism. Arch Intern Med 2007;167:74
  2. Ibrahaim et al. Thrombolytic Therapy and Mortality in Patients With Acute Pulmonary Embolism. Arch Intern Med 2008;168:2183 (inappropriate use of thrombolytics in low risk patients may increase mortality; see commentary)
  3. Wang 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;137:254(50 mg dose as effective as 100 mg dose, associated with less bleeding)
  4. Vendantham et al. Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis. NEJM 2017;377:2240(Treatment increased bleeding risk, did not significantly lower risk or post thrombotic syndrome or improve QOL; also see letters to editor)
  5. Campbell et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. NEJM 2018;378:1573(Tenecteplase superior)
  6. Impact of Female Sex on Death and Bleeding After Fibrinolytic Treatment of Myocardial Infarction in GUSTO V. Arch Intern Med 2007;167:2054
  7. Hemmelgarn et al. Prevention of dialysis catheter malfunction with recombinant tissue plasminogen activator. NEJM 2011;364:303
  8. Shahjouei et al. Safety of Intravenous Thrombolysis Among Patients Taking Direct Oral Anticoagulants. A Systematic Review and Meta-Analysis. Stroke 2019 (Epub).

Anticoagulant drugs: causes and treatment of bleeding and other complications

  1. Tomaselli et al. 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020 (Epub)
  2. Klok and Huisman. How I assess and manage the risk of bleeding in patients treated for venous thromboembolism. Blood 2020;135:724
  3. den Exter et al. Management of bleeding risk in patients who receive anticoagulant therapy for venous thromboembolism: Communication from the ISTH SSC Subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease. J Thromb Haemost 2022;20:1910
  4. Khan et al. Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism. A Systematic Review and Meta-analysis. Ann Intern Med 2021;174:1420
  5. Nishimoto et al. Validation of the VTE‐BLEED score’s long‐term performance for major bleeding in patients with venous thromboembolisms: From the COMMAND VTE registry. J Thromb Haemost 2020;18:624
  6. Adam et al. Novel bleeding risk score for patients with atrial fibrillation on oral anticoagulants, including direct oral anticoagulants. J Thromb Haemost 2021;19:931(Age >75, HTN, Hx of cancer, Hx of major bleeding contribute to risk score)
  7. Frontera et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage. A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2015 (Epub)
  8. Epstein NE When to stop anticoagulation, anti-platelet aggregates, and non-steroidal anti-inflammatories (NSAIDs) prior to spine surgery. Surg Neurol Int 2019 (Epub)
  9. Anderson and Cifu. Management of Bleeding in Patients Taking Oral Anticoagulants. JAMA 2018;319:2032
  10. Piran and Schulman. Treatment of bleeding complications in patients on anticoagulant therapy. Blood 2019;133:425
  11. Arachchillage et al. Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding. Br J Haematol 2018 (Epub)(PCC equally effective and safe to reverse all three drugs; 30 day mortality 35%)
  12. Scherz et al. Prospective, multicenter validation of prediction scores for major bleeding in elderly patients with venous thromboembolism. J Thromb Haemost 2013;11:435(Existing bleeding scores not able to predict bleeding accurately in elderly patients; with useful editorialthat describes a common-sense approach to this problem)
  13. Carrier et al. Systematic Review: Case-Fatality Rates of Recurrent Venous Thromboembolism and Major Bleeding Events Among Patients Treated for Venous Thromboembolism. Ann Intern Med 2010;152:578(Benefits of anticoagulation outweigh risks only if recurrence rate more than 3-fold higher than bleeding risk)
  14. Riva 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;112:511
  15. de Jong et al. Incidence and impact of anticoagulation-associated abnormal menstrual bleeding in women after venous thromboembolism. Blood 2022;140:1764 (66% of women 18-50 had abnormal uterine bleeding while anticoagulated)
  16. Boonyawat et al. How I treat heavy menstrual bleeding associated with anticoagulants. Blood 2017;130:2603
  17. Frey et al. Physical activity and risk of bleeding in elderly patients taking anticoagulants. J Thromb Haemost 2015;13:197(Higher level of activity associated with lower bleeding risk)
  18. Davidson et al. Bleeding Risk of Patients With Acute Venous Thromboembolism Taking Nonsteroidal Anti-Inflammatory Drugs or Aspirin. JAMA Intern Med 2014;174:947(1.7-fold increase in bleeding risk when NSAIDs or ASA added to anticoagulant therapy)
  19. Dalgaard et al. Patients With Atrial Fibrillation Taking Nonsteroidal Anti-Inflammatory Drugs and Oral Anticoagulants in the ARISTOTLE Trial. Circulation 2020;141:10  (1.6-fold increase in major bleeding – but not GI bleeding – when NSAID take along with a DOAC)
  20. Vanassche et al. Organ-specific bleeding patterns of anticoagulant therapy: lessons from clinical trials. Thromb Haemost 2014;112:918‘
  21. Deitelzweig et al. Comparison of major bleeding risk in patients with non-valvular atrial fibrillation receiving direct oral anticoagulants in the real-world setting: a network meta-analysis. Curr Med Res Opin 2017 (Epub)(DOACs caused less major bleeding than warfarin; apixaban associated with lowest risk)
  22. van Rein et al. Major Bleeding Rates in Atrial Fibrillation Patients on Single, Dual, or Triple Antithrombotic Therapy. Results From a Nationwide Danish Cohort Study. Circulation 2019;139:775 (2.3-fold higher bleed risk for DOAC + DAPT, 3.7-fold higher risk for VKA + DAPT)
  23. Pottegård et al. Antithrombotic drugs and subarachnoid haemorrhage risk. A nationwide case-control study in Denmark. Thromb Haemost 2015;114:1064(ASA, clopidogrel and VKA only associated with increased risk of SAH in first three months of treatment)
  24. Gaist et al. Association of Antithrombotic Drug Use With Subdural Hematoma Risk. JAMA 2017;317:836(Risk doubles with antithrombotic Rx, highest with VKA + antiplatelet drug and VKA in older pts)
  25. Gulati et al. Risk of intracranial hemorrhage (RICH) in users of oral antithrombotic drugs: Nationwide pharmacoepidemiological study. PLOS One 2018;13:e0202575
  26. Wu et al. Risk of intracranial hemorrhage with direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Neurol 2021 (Epub). (All DOACS safer than VKAs. Apixaban and dabigatran as safe as ASA)
  27. Hawryluk et al. Management of anticoagulation following central nervous system hemorrhage in patients with high thromboembolic risk. J Thromb Haemost 2010;8:1500 (Restarting before 72 h associated with more bleeding; restarting after 72 h associated with more thrombosis)
  28. Grainger et al. Between a rock and a hard place: resumption of oral anticoagulant therapy after intracranial hemorrhage. J Thromb Haemost 2024;22:594
  29. Kaisaier et al. Effect of oral anticoagulant therapy on adverse outcomes in atrial fibrillation patients after intracranial haemorrhage.  Heart Rhythm 2025 (Epub) (Increased bleed risk, no difference in stroke or other vascular events with restarting anticoagulation in this meta-analysis)
  30. Lopes et al. Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy. Blood 2017;129:2980(ICH risk higher in warfarin-treated patients than with apixaban, regardless of the adequacy of INR control)
  31. Kuramatsu et al. Anticoagulant Reversal, Blood Pressure Levels, and Anticoagulant Resumption in Patients With Anticoagulation-Related Intracerebral Hemorrhage. JAMA 2015;313:824(Reversal within 4h, good BP control associated with smaller hematomas; restarting anticoagulants after 3-4 weeks generally safe, associated with fewer ischemic events)
  32. Nielsen et al. Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality, and Bleeding. A Nationwide Cohort Study. Circulation 2015;132:517(Better outcomes if anticoagulants are restarted)
  33. Paciaroni et al. Efficacy and safety of anticoagulants in the prevention of venous thromboembolism in patients with acute cerebral hemorrhage: a meta-analysis of controlled studies. J Thromb Haemost 2011;9:893(Significant reduction in PE, non-significant decrease in mortality, increased risk of enlarging hematoma)
  34. Albrecht et al. Benefits and Risks of Anticoagulation Resumption Following Traumatic Brain Injury. JAMA Intern Med 2014;174:1244(Net benefit from re-starting warfarin following discharge, despite increased bleeding risk)
  35. Donato et al. Intracranial hemorrhage in patients with brain metastases treated with therapeutic enoxaparin: a matched cohort study. Blood 2015;126:494(Therapeutic anticoagulation does not increase risk of ICH in patients with brain mets)
  36. Zwicker et al. A meta-analysis of intracranial hemorrhage in patients with brain tumors receiving therapeutic anticoagulation. J Thromb Haemost 2016;14:1736(Anticoagulation did not increase risk of IC bleeding with brain mets but increased risk 4x with gliomas)
  37. Ray et al. Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding. JAMA 2018;320:2221(PPI lowered risk of GI bleeding by about one-third; rivaroxaban had highest GIB risk)
  38. Chai-Adisaksopha et al. Thromboembolic events, recurrent bleeding and mortality after resuming anticoagulant following gastrointestinal bleeding. A meta-analysis. Thromb Haemost 2015;114:657(Restarting warfarin after GI bleed reduces thromboembolism and mortality, no significant increase in recurrent GI bleed rate)
  39. Kido and Scalese. Management of Oral Anticoagulation Therapy After Gastrointestinal Bleeding: Whether to, When to, and How to Restart an Anticoagulation Therapy. Ann Pharmacother 2017 (Epub)(Restarting therapy recommended after a 7-14 day interruption)
  40. Tapaskar et al. Restarting Warfarin versus Direct Oral Anticoagulants after Major Gastrointestinal Bleeding and Associated Outcomes in Atrial Fibrillation: A Cohort Study. Clin Gastroenterol Hepatol 2020 (Epub)(Restarting warfarin or rivaroxaban caused more recurrent bleeding than restarting apixaban or dabigatran)
  41. Xu and Siegal. Anticoagulant-associated gastrointestinal bleeding: Framework for decisions about whether, when and how to resume anticoagulants. J Thromb Haemost 2021;19:2383
  42. Candeloro et al. Recurrent bleeding and thrombotic events after resumption of oral anticoagulants following gastrointestinal bleeding: Communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost 2021;19:2628(Lower mortality if anticoagulation restarted despite higher bleeding rate)
  43. Lamberts et al. Bleeding After Initiation of Multiple Antithrombotic Drugs, Including Triple Therapy, in Atrial Fibrillation Patients Following Myocardial Infarction and Coronary Intervention. A Nationwide Cohort Study. Circulation 2012;126:1185(Persistently high bleeding risk, “no safe therapeutic window”)
  44. Shehab et al. National Estimates of Emergency Department Visits for Hemorrhage-Related Adverse Events From Clopidogrel Plus Aspirin and From Warfarin. Arch Intern Med 2010;170:1926(1.2% of patients on dual antiplatelet therapy required emergency attention for acute bleeding, vs 2.5% of those on warfarin)
  45. Abraham et al. Risk of Lower and Upper Gastrointestinal Bleeding, Transfusions, and Hospitalizations With Complex Antithrombotic Therapy in Elderly Patients. Circulation 2013;128:1869(Combining antithrombotic drugs increases UGI bleed risk by 40-60%, LGI bleed risk by30%)
  46. Wallis et al. Association Between Use of Antithrombotic Medication and Hematuria-Related Complications. JAMA 2017;318:1260
  47. Bhatt et al. Incidence of Visible Haematuria among Antithrombotic Agents: a Systematic Review of Over 175,000 Patients. Urology 2017 (Epub)
  48. Kalathottukaren et al. Comparison of reversal activity and mechanism of action of UHRA, andexanet, and PER977 on heparin and oral FXa inhibitors. Blood Adv 2018l;2:2104

Protamine

  1. Levy et al. What’s fishy about protamine? Clinical use, adverse reactions, and potential alternatives. J Thromb Haemost 2023;21:1714

Warfarin/Vitamin K antagonists

  1. Kooistra et al; Risk of Bleeding and Thrombosis in Patients 70 Years or Older Using Vitamin K Antagonists. JAMA Int Med 2016;176:1176 (Bleeding risk only mildly increased past age 80, but thrombotic risk rose sharply)
  2. Witt et al. Risk of Thromboembolism, Recurrent Hemorrhage, and Death After Warfarin Therapy Interruption for Gastrointestinal Tract Bleeding. Arch Intern Med 2012;172:1484(Warfarin resumption within 90 days associated with lower risk of thrombosis and death)
  3. Nielsen et al. Outcomes Associated With Resuming Warfarin Treatment After Hemorrhagic Stroke or Traumatic Intracranial Hemorrhage in Patients With Atrial Fibrillation. JAMA Intern Med 2017;177:563(Resuming warfarin reduced thromboembolic risk, increased ICH risk after hemorrhagic stroke but not after traumatic bleed)
  4. Van Den Ham et al. The patterns of anticoagulation control and the risk of stroke, bleeding and mortality in patients with non-valvular atrial fibrillation. J Thromb Haemost 2013;11:107(Unstable INR → 11-fold increased mortality)
  5. Warkentin et al. Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta-analysis. J Thromb Haemost 2012;10:512(Overall bleeding risk similar with each drug, risk of intracranial bleeding higher with warfarin)
  6. Fischer et al. Hemorrhage During Warfarin Therapy Associated With Cotrimoxazole and Other Urinary Tract Anti-infective Agents. Arch Intern Med 2010;170:617(TMP Sulfa associated with higher bleeding risk than other commonly used antibiotics in warfarin-treated pts)
  7. Hylek et al. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med 2000;160:1612(INR > 6 associated with 4.4% of major bleeding)
  8. Lind et al. Thrombomodulin as a Marker for Bleeding Complications During Warfarin Treatment. Arch Intern Med 2009;169:1210
  9. De et al. Association of Genetic Variants With Warfarin-Associated Bleeding Among Patients of African Descent. JAMA 2018;320:1670
  10. Greinacher et al. Reversal of anticoagulants: an overview of current developments. Thromb Haemost 2015;113:911
  11. Lubetsky et al. Comparison of Oral vs Intravenous Phytonadione (Vitamin K1) in Patients With Excessive Anticoagulation. A Prospective Randomized Controlled Study. Arch Intern Med. 2003;163:2469
  12. DeZee et al. Treatment of Excessive Anticoagulation With Phytonadione (Vitamin K). A Meta-analysis. Arch Intern Med 2006;166:391
  13. Crowther et al. Oral Vitamin K Versus Placebo to Correct Excessive Anticoagulation in Patients Receiving Warfarin. A Randomized Trial. Ann Intern Med 2009;150:293(vit K did not reduce bleeding rates in non-bleeding patients with INRs between 4.5 and 10)
  14. Farrow et al. Vitamin K versus warfarin interruption alone in patients without bleeding and an international normalized ratio > 10. J Thromb Haemost 2020;18:1133 (Vit K did not improve outcomes in asymptomatic patients with INR > 10)
  15. Rashidi and Tahhan. Fresh frozen plasma dosing for warfarin reversal: a practical formula. Mayo Clin Proc 2013;88:244
  16. Hickey et al. Outcomes of Urgent Warfarin Reversal With Frozen Plasma Versus Prothrombin Complex Concentrate in the Emergency Department. Circulation 2013;128:360(PCC caused faster reversal, less need for RBC transfusion)
  17. Chai-Adisaksopha et al. Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. Thromb Haemost 2016;116:879(PCC reduces overall mortality, corrects INR more quickly, and causes less volume overload without increasing risk of thrombosis)
  18. Goldstein et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015;385:2077(Rapid INR reduction in 55% of patients getting PCC vs 10% of those getting FFP)
  19. Marshall et al. Dose-associated pulmonary complication rates after fresh frozen plasma administration for warfarin reversal. J Thromb Haemost 2016;14:324(20% incidence of TACO; risk higher if > 3 U FFP transfused)
  20. Sarode et al. Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting With Major Bleeding. A Randomized, Plasma-Controlled, Phase IIIb Study. Circulation 2013;128:1234(PCC much more effective, equally safe)
  21. Skolnick et al. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood 2010;116:693(rVIIa did not reduce warfarin-related blood loss)

DOACs

  1. Levy et al. Reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2024;22:2889
  2. Godier and Martin. Specific Antidotes for Direct Oral Anticoagulant Reversal. Case Closed or Cold Case? Circulation 2019;140:1445
  3. Ruff et al. Management of Bleeding With Non–Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents. Circulation 2016;134: 248
  4. Tchen et al. Validation of Bleeding Risk Prediction Scores for Patients With Major Bleeding on Direct Oral Anticoagulants. Ann Pharmacother 2020 (Epub)(Most published risk scores have only modest predictive value)
  5. Testa et al. Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost 2019;17:1064(Higher peak levels associated with bleeding risk)
  6. Nguyen et el. Evaluation of Anti-Xa Apixaban and Rivaroxaban Levels With Respect to Known Doses in Relation to Major Bleeding Events. J Pharm Pract 2021 (Epub)(Bleeding associated with advanced age, low body weight, and acute renal impairment. Concomitant azole antifungal use associated with high blood levels and one fatal bleed)
  7. Ingason et al. Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants. A Nationwide Propensity Score–Weighted Study. Ann Intern Med 2021 (Epub)
  8. Valeriani et al. Impact of concomitant antiplatelet therapy on the efficacy and safety of direct oral anticoagulants for acute venous thromboembolism: Systematic review and meta‐analysis. J Thromb Haemost 2020;18:1661(Adding antiplatelet drug to DOAC increases bleed risk, does not lower VTE risk)
  9. Schaefer et al. Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication. JAMA Intern Med 2021;181:817
  10. Naito et al. Rivaroxaban Monotherapy vs Combination Therapy With Antiplatelets on Total Thrombotic and Bleeding Events in Atrial Fibrillation With Stable Coronary Artery Disease.  A Post Hoc Secondary Analysis of the AFIRE Trial. JAMA Cardiol 2022;7:787 (Rivaroxaban monotherapy associated with 38% lower incidence of total adverse events than combined therapy)
  11. Xiong et al. Association between platelet count and the risk of bleeding among patients with nonvalvular atrial fibrillation taking dabigatran after radiofrequency ablation: a cohort study. Cardiovasc Diagn Ther 2020;10:1175(Platelet counts below 100K associated with higher bleed risk; most bleeds minor)
  12. Majeed et a. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017;130:1706(70% effective, low rate of thrombosis)
  13. Barco et al. In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate. Br J Haem 2016;172:255(Partial restoration of thrombin generation at dose of 37.5 iu/kg, not at lower dose)
  14. Song et al. Reversal of apixaban anticoagulation by four-factor prothrombin complex concentrates in healthy subjects: a randomized three-period crossover study. J Thromb Haemost 2017;15: 2125
  15. Schulman et al. Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study. Thromb Haemost 2018 (Epub)(PCC considered to have good or moderate efficacy in 85% of patients; 8% had major thromboembolic event)
  16. Levy et al. Rivaroxaban reversal with prothrombin complex concentrate or tranexamic acid in healthy volunteers. J Thromb Haemost 2018;16:54(4 factor PCC, but not TXA, improved laboratory indices of coagulation; neither reduced skin bleeding after punch biopsy)
  17. Arellano-Rodrigo et al. Coagulation Factor Concentrates Fail to Restore Alterations in Fibrin Formation Caused by Rivaroxaban or Dabigatran in Studies With Flowing Blood From Treated Healthy Volunteers. Transfus Med Rev 2015 (Epub)
  18. Zahir et al. Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate. Circulation 2015;131:82(50 IU/kg of PCC reversed edoxaban effect on bleeding duration)
  19. Zada et al. Four-Factor Prothrombin Complex Concentrate for the Reversal of Direct Oral Anticoagulants. J Intensive Care Med 2019 (Epub).(85% of 53 patients had “positive response”)
  20. Green et al. Haematological management of major bleeding associated with direct oral anticoagulants – UK experience. Br J Haem 2019;Epub(Administration of PCC did not significantly impact in-hospital mortality)
  21. Panos et al. Factor Xa Inhibitor-Related Intracranial Hemorrhage. Results From a Multicenter, Observational Cohort Receiving Prothrombin Complex Concentrates. Circulation 2020;141:1681(“Excellent or good” hemostasis in 82% of patients, but high rates of mortality and disability; with editorial)
  22. Hunt et al. Factor VIII Inhibitor Bypassing Activity (FEIBA) Reversal for Apixaban and Rivaroxaban in Patients With Acute Intracranial and Nonintracranial Hemorrhage. Ann Pharmacother 2021 (Epub)(89% had “effective hemostasis”, 8% had thromboembolism, 13% mortality)
  23. Ruff et al. Management of Bleeding With Non–Vitamin K Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents. Circulation 2016; 134:248
  24. Hunt et al. Reversing anti–factor Xa agents and the unmet needs in trauma patients. Blood 2018;132:2441
  25. Levy et al. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016;14:623
  26. Majeed et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013;128:2325(Bleeding from dabigatran required more RBC, less plasma, and had trend toward lower mortality than bleeding from warfarin)
  27. Beyer-Westendorf et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014;124:955(Major bleeding rates somewhat lower than for VKAs and outcomes not worse; benefits of PCC administration appear modest)
  28. Chai-Adisaksopha et al. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014;124:2450(DOACs cause less bleeding than VKAs; no increase in risk of GI bleeding)
  29. Radadiya et al. Major gastrointestinal bleeding risk with direct oral anticoagulants: Does type and dose matter? – A systematic review and network meta-analysis. Eur J Gastroenterol Hepatol 2021 (Epub) (Suggests that dabigatran and rivaroxaban create higher risk of GI bleeding than warfarin, whereas apixaban does not)
  30. Becattini et al. Variation of renal function over time is associated with major bleeding in patients treated with direct oral anticoagulants for atrial fibrillation. J Thromb Haemost 2018;16:833
  31. Beyer-Westendorf et al. Management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on direct oral anti-factor Xa inhibitor therapy: a case series. Lancet Haematol 2016;3:e480(About a third of women at risk have excessive vaginal bleeding on Xa inhibitors. Look for anatomic abnormalities when bleeding is severe or recurrent)
  32. Böhm et al. Cardiovascular outcomes, bleeding risk, and achieved blood pressure in patients on long-term anticoagulation with the thrombin antagonist dabigatran or warfarin: data from the RE-LY trial. (Low BP associated with more bleeding, worse outcomes. High BP did not predict bleeding)
  33. Chen et al. Anticoagulant-related nephropathy induced by direct-acting oral anticoagulants: Clinical characteristics, treatments and outcomes. Thromb Res 2023;222:20

Idaracizumab

  1. Glund et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015;113:911
  2. Pollack et al. Idarucizumab for Dabigatran Reversal. NEJM 2015;373:511(With editorial)
  3. Pollack et al. Idarucizumab for Dabigatran Reversal — Full Cohort Analysis. NEJM 2017;377:431(All patients had 100% reversal of anticoagulant effect on clotting times; a few patients had rebound anticoag effect requiring another dose after 12-24h)
  4. van der Waal et al. Idarucizumab for Dabigatran Reversal in the Management of Patients with Major Gastrointestinal Bleeding. Circulation 2018 (Epub)

Andexanet

  1. Connolly et al. Andexanet for Factor Xa Inhibitor–Associated Acute Intracerebral Hemorrhage. NEJM 2024;390:1745 (RCT comparing andexanet to “standard care” – mainly PCC.  Better “hemostatic efficacy” with andexanet but more thrombotic events. No difference in survival or neuro outcomes.  With editorial)
  2. Panos et al. Reversal of Factor Xa Inhibitor-Related Intracranial Hemorrhage: A Multicenter, Retrospective, Observational Study Comparing the Efficacy and Safety of Andexanet and Prothrombin Complex Concentrates. Crit Care Med 2025 (Epub) (Similar results to above trial – more thrombotic events with andexanet and no difference in overall outcomes)
  3. Siegal et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. NEJM 2015;373:2413(With editorial)
  4. Connolly et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. NEJM 2016;375:1131(with editorial)
  5. Connolly et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. NEJM 2019;380:1326
  6. Milling et al. Final Study Report of Andexanet Alfa for Major Bleeding With Factor Xa Inhibitors. Circulation 2023 (Epub)
  7. Nederpelt et al. Evaluation of oral factor Xa inhibitor‐associated extracranial bleeding reversal with andexanet alfa. J Thromb Haemost 2020;18:2532 (Retrospective study of 77 patients with overall poor outcomes, high rate of ischemic complications)
  8. Lu et al. A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers. Blood Adv 2020;4:728
  9. Costa et al. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis. Crit Care 2022; 26:180
  10. Demchuck et al. Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage. Stroke 2021;52:2096
  11. Markovic et al. Time to hemostatic agent administration increases mortality in veterans with factor Xa inhibitor-related intracranial hemorrhage. Am J Emerg Med 2025;98:201

Ciraparantag

  1. Ansell et al. Use of PER977 to reverse the anticoagulant effect of edoxaban (letter). NEJM 2014;371:2141 (Ciraparantag)
  2. Ansell et al. Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost 2017;117:238
  3. Ansell et al. Ciraparantag, an anticoagulant reversal drug: mechanism of action, pharmacokinetics, and reversal of anticoagulants. Blood 2021;137:115

Other reversal agents

  1. Thalji et al. A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nat Med 2016;22: 924

Antiplatelet drugs

  1. Berger et al. Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease. Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial. Circulation 2010;121:2575
  2. Cea Soriano et al. Incidence of intracranial bleeds in new users of low-dose aspirin: a cohort study using The Health Improvement Network. J Thromb Haemost 2017;15:1055(0.08 episodes per 100 person-years)
  3. Melkonian et al. Bleeding risk of antiplatelet drugs compared with oral anticoagulants in older patients with atrial fibrillation: a systematic review and meta-analysis. J Thromb Haemost 2017;15:1500(Risk of major bleeding appears similar with antiplatelet and anticoagulant drugs in patients over 65; intracranial bleeding risk higher with warfarin)
  4. Li et al. Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study. Lancet 2017; 390:490(Older patients at relatively high risk for major UGI bleeding if not prescribed PPI)
  5. Feely et al. Safety of clopidogrel in hip fracture surgery. Mayo Clin Proc 2013;88:149
  6. Steinhubl et al. Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding. Ann Intern Med 2009;150:379
  7. García Rodríguez et al. Risk of Upper Gastrointestinal Bleeding With Low-Dose Acetylsalicylic Acid Alone and in Combination With Clopidogrel and Other Medications. Circulation 2011;123:1108
  8. Vilahur et al. Normalization of platelet reactivity in clopidogrel-treated subjects. J Thromb Haemost 2007;5:82(Using platelet transfusion to reverse clopidogrel effect)
  9. Baharoglu et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet 2016;387:2605(Worse outcomes with platelet transfusion in this setting; with editorial)
  10. Baschin et al. Preoperative platelet transfusions to reverse antiplatelet therapy for urgent non‐cardiac surgery: an observational cohort study. J Thromb Haemost 2018;16:709(No coronary thrombosis, 12% bleeding incidence with administration of 2 platelet units pre-op in this non-randomized study.)
  11. Teng et al. Effects of autologous platelet transfusion on platelet inhibition in ticagrelor-treated and clopidogrel-treated subjects. J Thromb Haemost 2016;14:2342(No evidence of benefit)
  12. Bertling et al. Reversibility of platelet P2Y12 inhibition by platelet supplementation: ex vivo and in vitro comparisons of prasugrel, clopidogrel and ticagrelor. J Thromb Haemost 2018;16:1089(Ticagrelor effect more difficult to reverse than that of prasugrel or clopidogrel)
  13. Bhatt et al. Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers. NEJM 2019;380:1825
  14. Tcheng JE. Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: Bleeding, reversal, thrombocytopenia, and retreatment. Am Heart J 2000;139:s38
  15. RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet 2019;393:2613(Restarting antiplatelet Rx soon after hemorrhagic stroke is safe)

Management of anticoagulation for surgery, etc.

  1. Douketis et al. Perioperative Management of Antithrombotic Therapy. An American College of Chest Physicians Clinical Practice Guideline. Chest 2022 (Epub)
  2. Shah et al. Perioperative Management of Vitamin K Antagonists and Direct Oral Anticoagulants: A Systematic Review and Meta-analysis. Chest 2022 (Epub)
  3. Douketis and  Spyropoulos. Perioperative Management of Patients Taking Direct Oral Anticoagulants. A Review.  JAMA 2024 (Epub)
  4. Parks and Fang.  Periprocedural anticoagulation.  Ann Intern Med 2023;176:ITC49
  5. Berry et al. The bridging conundrum: perioperative management of direct oral anticoagulants for venous thromboembolism. J Thromb Haemost 2023;21:780
  6. Douketis et al. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med 2019; 179:1469 (PAUSE trial)
  7. Shaw et la. Predictors of preprocedural direct oral anticoagulant levels in patients having an elective surgery or procedure. Blood Adv 2020;4:3520 (Data from thee PAUSE trial)
  8. Paikin et al. Timing the first post-operative dose of anticoagulants: Lessons learned from clinical trials. Chest 2015 (ePub)(Wait at least 6 hours after surgery to begin prophylaxis with DOAC)
  9. Douketis et al. Perioperative bridging in patients with atrial fibrillation. NEJM 2015;373:823(No increase in thromboembolism without bridging, less major bleeding)
  10. Douketis et al. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med 2019;179:1469(DOACs omitted 1-2 days prior to procedure with no bridging, with low rates of bleeding or thromboembolism)
  11. Al-Khatib et al. Duration of Anticoagulation Interruption Before Invasive Procedures and Outcomes in Patients With Atrial Fibrillation: Insights From the ARISTOTLE Trial.  Circulation 2022;156:958 (2-3 day interruption of apixaban gave best outcomes)
  12. Clark et al. Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures. JAMA Intern Med 2015; 175:1163(More bleeding, no significant reduction in recurrent VTE with bridging; retrospective study, with editorial)
  13. Douketis et al. Low-Molecular-Weight Heparin as Bridging Anticoagulation During Interruption of Warfarin. Assessment of a Standardized Periprocedural Anticoagulation Regimen. Arch Intern Med 2004;164:1319
  14. Douketis et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial. J Thromb Haemost 2015;113:437(Bridging increased bleed risk, did not affect thrombosis rate)
  15. Kim et al. Heparin bridging in warfarin anticoagulation therapy initiation could increase bleeding in non-valvular atrial fibrillation patients: a multicenter propensity-matched analysis. J Thromb Haemost 2015;13:182(Stroke rates similar, bleeding rate higher with bridging)
  16. Dunn et al. Bridging therapy in patients on long-term oral anticoagulants who require surgery: the Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). J Thromb Haemost 2007;5:2211 (Non-randomized trial of enoxaparin 1.5 mg/kg prior to surgery – 20% major bleeds with major surgery)
  17. Garcia et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med 2008;168:63(Risk of thrombosis low, comparable to risk of major bleeding if bridging anticoagulation given)
  18. Lee et al. Outcomes in patients undergoing periprocedural interruption of warfarin or direct oral anticoagulants. J Thromb Haemost 2022;20:2571 (More bleeding in DOAC group than in the unbridged warfarin group)
  19. Skeith et al. Conservative perioperative anticoagulation management in patients with chronic venous thromboembolic disease: a cohort study. J Thromb Haemost 2012;2298 (Interruption of warfarin, no pre-op LMWH, post-op LMWH only for hospitalized pts appeared safe in this non-randomized study)
  20. Birnie et al. Pacemaker or Defibrillator Surgery without Interruption of Anticoagulation. NEJM 2013;368:2084(Safer to continue warfarin than to bridge with heparin or LMWH)
  21. Passaglia et al. Early postoperative bridging anticoagulation after mechanical heart valve replacement: a systematic review and meta-analysis. J Thromb Haemost 2015;13:1557(Modest decrease in thromboembolism and increase in bleeding with bridging)
  22. Tafur et al. Predictors of major bleeding in peri-procedural anticoagulation management. J Thromb Haemost 2012;10:261(Bridging and restarting heparin within 24 hours of procedure increase bleeding risk)
  23. Siegal et al. Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists. Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates. Circulation 2012;126:1630(Bridging associated with higher bleeding risk, similar risk of thromboembolism vs no bridging)
  24. Steinberg et al. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Circulation 2015;131:488(Higher rates of bleeding and adverse events when bridging used. “These data do not support the use of routine bridging”. With editorial)
  25. Beyer-Westendorf et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014; (ePub)(Higher risk of bleeding with heparin bridging, unclear benefit; continuation or brief interruption of NOAC safe for most procedures)
  26. Mathew et al. Efficacy and safety of early parenteral anticoagulation as a bridge to warfarin after mechanical valve replacement. Thromb Haemost 2014;112:1077(Bridging with therapeutic heparin caused more bleeding, did not lower rate of thromboembolism)
  27. O’Donnell et al. Preoperative Anticoagulant Activity after Bridging Low-Molecular-Weight Heparin for Temporary Interruption of Warfarin. Ann Intern Med 2007;146:184 (Heparin levels high during surgery if LMWH continued until night prior to surgery)
  28. Leijtens et al. High complication rate after total knee and hip replacement due to perioperative bridging of anticoagulant therapy based on the 2012 ACCP guideline. Arch Orthop Trauma Surg 2014;134:1335
  29. Sherwood et al. Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation. Circulation 2014;129:1850(Risk of stroke or embolism < 0.5% per 30 days with discontinuation of either drug)
  30. Aziz et al. Thrombotic and bleeding outcomes following the perioperative interruption of anticoagulation among patients with nonvalvular atrial fibrillation and active cancer. J Thromb Haemost 2023;21:933 (“Contemporary perioperative anticoagulation practices appear safe among atrial fibrillation patients with cancer”)
  31. Takeuchi et al. Continuous Anticoagulation and Cold Snare Polypectomy Versus Heparin Bridging and Hot Snare Polypectomy in Patients on Anticoagulants With Subcentimeter Polyps: A Randomized Controlled Trial. Ann Intern Med 2019;171:229(Less bleeding in non-bridging cohort)
  32. Brennan et al. Dental extractions on direct oral anticoagulants vs. warfarin: The DENTST study. Res Pract Thromb Haemost 2020;4:278 (No need to adjust DOAC dosing prior to dental procedures)
  33. Curtis et al. Management of antithrombotic therapy in patients undergoing dental procedures. J Thromb Haemost 2025;23:47
  34. Shaw et al. Coagulation assays and direct oral anticoagulant levels among patients having an elective surgery or procedure. J Thromb Haemost 2022;20:2953 (PT/INR and PTT poor predictors of DOAC levels)
  35. Wang et al. Peri-procedure management of antithrombotic agents and thrombocytopenia for common procedures in oncology: Guidance from the SSC of the ISTH. J Thromb Haemost 2022;20:3026
  36. Shaw et al. Periprocedural management of direct oral anticoagulants in patients with atrial fibrillation and active cancer. J Thromb Haemost 2024;22:727
  37. Bishay et al. Incidence, Predictors, and Outcomes of Clinically Significant Post-ERCP Bleeding: a Contemporary Multi-center Study. Am J Gastroenterol 2024 (Epub)
  38. Mair et al. Impact of elevated direct factor Xa inhibitor plasma levels on perioperative blood loss in patients undergoing urgent surgery. Transfusion 2024 (Epub) (Retrospective study with n=32. Blood loss not markedly worse in noncardiac surgery despite high anti-Xa levels)
  39. Schulman et al. Prothrombin complex concentrate for emergency surgery in patients on oral Xa-inhibitors. J Thromb Haemost 2024;22:2761