Abstract
Half of all patients with acute venous thromboembolism are aged over 70 years; they then face the added hazard of an age-related increase in the incidence of major bleeding. This makes it even more important to weigh the balance of benefit and risk when considering anticoagulant treatment and treatment duration. Traditional treatment with a heparin (usually low molecular weight) followed by a vitamin K antagonist such as warfarin is effective but is often complicated, especially in the elderly. The direct-acting oral anticoagulants (DOACs), i.e. the thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban and edoxaban, are given in fixed doses, do not need laboratory monitoring, have fewer drug–drug interactions and are therefore much easier to take. Randomised trials, their meta-analyses and ‘real-world’ data indicate the DOACs are no less effective than warfarin (are non-inferior) and probably cause less major bleeding (especially intracranial). It seems the relative safety of DOACs extends to age above 65 or 70 years, although bleeding becomes more likely regardless of the chosen anticoagulant. Renal impairment, comorbidities (especially cancer) and interventions are special hazards. Ways to minimise bleeding include patient selection and follow-up, education about venous thromboembolism, anticoagulants, drug interactions, regular checks on adherence and avoiding needlessly prolonged treatment. The relatively short circulating half-lives of DOACs mean that time, local measures and supportive care are the main response to major bleeding. They also simplify the management of invasive interventions. An antidote for dabigatran, idarucizumab, was recently approved by regulators, and a general antidote for factor Xa inhibitors is in advanced development.
Similar content being viewed by others
References
Raskob GE, Angchaisuksiri P, Blanco AN, Buller H, Gallus A, Hunt BJ, et al. Thrombosis: a major contributor to global disease burden. Semin Thromb Hemost. 2014;40(7):724–35.
Tagalakis V, Patenaude V, Kahn SR, Suissa S. Incidence of and mortality from venous thromboembolism in a real-world population: the Q-VTE Study Cohort. Am J Med 2013;126(9):832.e13–21.
Kearon C. Natural history of venous thromboembolism. Circulation. 2003;107(23 suppl 1):I-22–I-30.
Galanaud JP, Kahn SR. Postthrombotic syndrome: a 2014 update. Curr Opin Cardiol. 2014;29(6):514–9.
Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, et al. Venous thromboembolism (VTE) in EuropeL the number of VTE events and associated morbidity and mortality. Thromb Haemost. 2007;98(4):756–64.
Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD, Enright P, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med. 2004;117(1):19–25.
Barnes GD, Ageno W, Ansell J, Kaatz S. Subcommittee on the Control of A. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(6):1154–6.
Siguret V, Gouin-Thibault I, Gaussem P, Pautas E. Optimizing the use of anticoagulants (heparins and oral anticoagulants) in the elderly. Drugs Aging. 2013;30(9):687–99.
Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost. 2014;112(2):255–63.
Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost. 2000;83(5):657–60.
Huerta C, Johansson S, Wallander MA. Garcia Rodriguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med. 2007;167(9):935–43.
Spencer FA, Gore JM, Reed G, Lessard D, Pacifico L, Emery C, et al. Venous thromboembolism and bleeding in a community setting: the Worcester Venous Thromboembolism Study. Thromb Haemost. 2009;101(5):878–85.
Ho WK, Hankey GJ, Eikelboom JW. The incidence of venous thromboembolism: a prospective, community-based study in Perth, Western Australia. Med J Aust. 2008;189(3):144–7.
Jang MJ, Bang SM, Oh D. Incidence of venous thromboembolism in Korea: from the Health Insurance Review and Assessment Service database. J Thromb Haemost. 2011;9(1):85–91.
Lee CH, Lin LJ, Cheng CL, Kao Yang YH, Chen JY, Tsai LM. Incidence and cumulative recurrence rates of venous thromboembolism in the Taiwanese population. J Thromb Haemost. 2010;8(7):1515–23.
Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet. 1960;1(7138):1309–12.
Brandjes DP, Heijboer H, Buller HR, de Rijk M, Jagt H, ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1992;327(21):1485–9.
Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2010(9):CD001100.
Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism: a prospective cohort study in 1,626 patients. Haematologica. 2007;92(2):199–205.
Boutitie F, Pinede L, Schulman S, Agnelli G, Raskob G, Julian J, et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. Brit Med J. 2011;342:d3036.
Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S–94S.
Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med. 2000;160(22):3431–6.
Lecumberri R, Alfonso A, Jimenez D, Fernandez Capitan C, Prandoni P, Wells PS, et al. Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost. 2013;110(4):834–43.
Laliberte F, Coleman CI, Bookhart B, Lefebvre P, Cloutier M, Damaraju CV, et al. Weekly risk of venous thromboembolism recurrence in patients receiving oral anticoagulants. Curr Med Res Opin. 2014;30(8):1513–20.
Garcia DA, Baglin TP, Weitz JI, Samama MM, American College of Chest P. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e24S–43S.
Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care” nomogram: a randomized controlled trial. Ann Intern Med. 1993;119(9):874–81.
Kearon C, Ginsberg JS, Julian JA, Douketis J, Solymoss S, Ockelford P, et al. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA. 2006;296(8):935–42.
Gray E, Mulloy B, Barrowcliffe TW. Heparin and low-molecular-weight heparin. Thromb Haemost. 2008;99(5):807–18.
Boneu B, Caranobe C, Sie P. Pharmacokinetics of heparin and low molecular weight heparin. Baillieres Clin Haematol. 1990;3(3):531–44.
Becker RC, Spencer FA, Gibson M, Rush JE, Sanderink G, Murphy SA, et al. Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes. Am Heart J. 2002;143(5):753–9.
Chow SL, Zammit K, West K, Dannenhoffer M, Lopez-Candales A. Correlation of antifactor Xa concentrations with renal function in patients on enoxaparin. J Clin Pharmacol. 2003;43(6):586–90.
Schmid P, Brodmann D, Odermatt Y, Fischer AG, Wuillemin WA. Study of bioaccumulation of dalteparin at a therapeutic dose in patients with renal insufficiency. J Thromb Haemost. 2009;7(10):1629–32.
Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259–68.
Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S–88S.
Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med. 2010;152(9):578–89.
Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764–72.
EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Bernner B, Buller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–510.
EINSTEIN-PE Investigators, Buller HR, Prins MH, Lensing AW, Decousus H, Jacobson BF, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287–97.
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.
Hokusai-VTE Investigators, Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15.
Monreal M, Suarez C, Fajardo JA, Barba R, Uresandi F, Valle R, et al. Management of patients with acute venous thromboembolism: findings from the RIETE registry. Pathophysiol Haemost Thromb. 2003;33(5–6):330–4.
Gomez-Outes A, Terleira-Fernandez AI, Lecumberri R, Suarez-Gea ML, Vargas-Castrillon E. Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis. Thromb Res. 2014;134(4):774–82.
Wu C, Alotaibi GS, Alsaleh K, Linkins LA, McMurtry MS. Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants for secondary prevention. Thromb Res. 2015;135(2):243–8.
van Es N, Coppens M, Schulman S, Middeldorp S, Buller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124(12):1968–75.
Beyer-Westendorf J, Förster K, Pannach S, Ebertz F, Gelbricht V, Thieme C, et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood. 2014;124(6):955–62.
Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, 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(1):e12–21.
U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared with warfarin. 2014. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm. Accessed May 2016.
Tamayo S, Frank Peacock W, Patel M, Sicignano N, Hopf KP, Fields LE, et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol. 2015;38(2):63–8.
Camm AJ, Amarenco P, Haas S, Hess S, Kirchhof P, Kuhls S, et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J. 2016;37(14):1145–53.
Kardas P, Lewek P, Matyjaszczyk M. Determinants of patient adherence: a review of systematic reviews. Front Pharmacol. 2013;4:91.
Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23(8):1296–310.
Yao X, Abraham NS, Alexander GC, Crown W, Montori VM, Sangaralingham LR, et al. Effect of adherence to oral anticoagulants on risk of stroke and major bleeding among patients with atrial fibrillation. J Am Heart Assoc. 2016;5(2). doi:10.1161/JAHA.115.003074.
Lopez-Jimenez L, Montero M, Gonzalez-Fajardo J, Arcelus J, Suarez C, Lobo J, et al. Venous thromboembolism in very elderly patients: findings from a prospective registry (RIETE). Haematologica. 2006;91(8):1046–51.
Trujillo-Santos J, Schellong S, Falga C, Zorrilla V, Gallego P, Barron M, et al. Low-molecular-weight or unfractionated heparin in venous thromboembolism: the influence of renal function. Am J Med. 2013;126(5):425-34 e1.
Roberts LN, Patel RK, Arya R. Venous thromboembolism and ethnicity. Br J Haematol. 2009;146(4):369–83.
Dang MT, Hambleton J, Kayser SR. The influence of ethnicity on warfarin dosage requirement. Ann Pharmacother. 2005;39(6):1008–12.
You JH, Chan FW, Wong RS, Cheng G. Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation? Br J Clin Pharmacol. 2005;59(5):582–7.
Yasaka M, Minematsu K, Yamaguchi T. Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation. Intern Med. 2001;40(12):1183–8.
Yang L, Ge W, Yu F, Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement: a systematic review and meta analysis. Thromb Res. 2010;125(4):e159–66.
Lindh JD, Holm L, Andersson ML, Rane A. Influence of CYP2C9 genotype on warfarin dose requirements: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2009;65(4):365–75.
Geldhof V, Vandenbriele C, Verhamme P, Vanassche T. Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants. Thromb J. 2014;12:21.
Lega JC, Bertoletti L, Gremillet C, Boissier C, Mismetti P, Laporte S. Consistency of safety profile of new oral anticoagulants in patients with renal failure. J Thromb Haemost. 2014;12(3):337–43.
Black SA, Cohen AT. Anticoagulation strategies for venous thromboembolism: moving towards a personalised approach. Thromb Haemost. 2015;114(4):660–9.
Nielsen PB, Lane DA, Rasmussen LH, Lip GY, Larsen TB. Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol. 2015;104(5):418–29.
European Medicines Agency. EMEA/H/C/000829. Pradaxa: EPAR, product information. 2009. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf. Accessed May 2016.
European Medicines Agency. EMEA/H/C/002148. Eliquis: EPAR, product information. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf. Accessed May 2016.
European Medicines Agency. EMEA/H/C/002629. Lixiana: EPAR, product information. 2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002629/WC500189045.pdf. Accessed May 2016.
European Medicines Agency. EMEA/H/C/000944. Xarelto: EPAR, product information. 2009. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf. Accessed May 2016.
Wang K-L, Lip GYH, Lin S-J, Chiang C-E. Non-vitamin K antagonist oral anticoagulants for stroke prevention in Asian patients with nonvalvular atrial fibrillation: meta-analysis. Stroke. 2015;46(9):2555–61.
Fang MC, Go AS, Hylek EM, Chang Y, Henault LE, Jensvold NG, et al. Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study. J Am Geriatr Soc. 2006;54(8):1231–6.
Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–100.
Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011;58(4):395–401.
Kuijer PM, Hutten BA, Prins MH, Buller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med. 1999;159(5):457–60.
Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105(2):91–9.
Ruiz-Gimenez N, Suarez C, Gonzalez R, Nieto JA, Todoli JA, Samperiz AL, et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism: findings from the RIETE Registry. Thromb Haemost. 2008;100(1):26–31.
Nieto JA, Solano R, Ruiz-Ribó MD, Ruiz-Gimenez N, Prandoni P, Kearon C, et al. Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry. J Thromb Haemost. 2010;8(6):1216–22.
Burgess S, Crown N, Louzada ML, Dresser G, Kim RB, Lazo-Langner A. Clinical performance of bleeding risk scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin. J Thromb Haemost. 2013;11(9):1647–54.
Riva N, Bellesini M, Di Minno MN, Mumoli N, Pomero F, Franchini M, et al. Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism: a multicentre retrospective cohort study. Thromb Haemost. 2014;112(3):511–21.
Piovella C, Dalla Valle F, Trujillo-Santos J, Pesavento R, Lopez L, Font L, et al. Comparison of four scores to predict major bleeding in patients receiving anticoagulation for venous thromboembolism: findings from the RIETE registry. Intern Emerg Med. 2014;9(8):847–52.
Poli D, Antonucci E, Testa S, Cosmi B, Palareti G, Ageno W, 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(6):1053–8.
Loewen P, Dahri K. Risk of bleeding with oral anticoagulants: an updated systematic review and performance analysis of clinical prediction rules. Ann Hematol. 2011;90(10):1191–200.
Man-Son-Hing M, Nichol G, Lau A, Laupacis A. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med. 1999;159(7):677–85.
Oldgren J, Wallentin L, Alexander JH, James S, Jönelid B, Steg G, et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J. 2013;34(22):1670–80.
Davidson BL, Verheijen S, Lensing AW, Gebel M, Brighton TA, Lyons RM, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014;174(6):947–53.
Clark NP, Witt DM, Davies LE, et al. Bleeding, recurrent venous thromboembolism, and mortality risks during warfarin interruption for invasive procedures. JAMA Intern Med. 2015;175(7):1163–8.
Beyer-Westendorf J, Gelbricht V, Förster K, Ebertz F, Köhler C, Werth S, et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J. 2014;35(28):1888–96.
Douketis JD, Spyropoulos AC, Kaatz S, Becker RC, Caprini JA, Dunn AS, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373(9):823–33.
Tran H, Joseph J, Young L, McRae S, Curnow J, Nandurkar H, et al. New oral anticoagulants: a practical guide on prescription, laboratory testing and peri-procedural/bleeding management. Australasian Society of Thrombosis and Haemostasis. Intern Med J. 2014;44(6):525–36.
Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, et al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP), March 2013. Arch Cardiovasc Dis. 2013;106(6–7):382–93.
Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, 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(2 Suppl):e152S–84S.
Tran HA, Chunilal SD, Harper PL, Tran H, Wood EM, Gallus AS. An update of consensus guidelines for warfarin reversal. Med J Aust. 2013;198(4):198–9.
Makris M, Van Veen JJ, Tait CR, Mumford AD, Laffan M. British Committee for standards in H: guideline on the management of bleeding in patients on antithrombotic agents. Br J Haematol. 2013;160(1):35–46.
Heidbuchel H, Berti D, Campos M, Desteghe L, Freixo AP, Nunes AR, et al. Implementation of non-vitamin K antagonist oral anticoagulants in daily practice: the need for comprehensive education for professionals and patients. Thromb J. 2015;13:22.
Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. 2013;34(7):489b–98b.
van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, et al. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116–27.
Wang X, Mondal S, Wang J, Tirucherai G, Zhang D, Boyd RA, et al. Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects. Am J Cardiovasc Drugs. 2014;14(2):147–54.
Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ. 2012;344:e3054.
Ker K, Roberts I, Shakur H, Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2015;5:Cd004896.
Lee FM, Chan AK, Lau KK, Chan HH. Reversal of new, factor-specific oral anticoagulants by rFVIIa, prothrombin complex concentrate and activated prothrombin complex concentrate: a review of animal and human studies. Thromb Res. 2014;133(5):705–13.
Khadzhynov D, Wagner F, Formella S, Wiegert E, Moschetti V, Slowinski T, et al. Effective elimination of dabigatran by haemodialysis: a phase I single-centre study in patients with end-stage renal disease. Thromb Haemost. 2013;109(4):596–605.
Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–20.
Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413–24.
Costin JC, Laulicht B, Bakhru S, Steiner S. PER977 reverses low molecular weight heparin in addition to IIA and XA new oral anticoagulants. J Am Coll Cardiol. 2015;65(10_S). doi:10.1016/S0735-1097(15)62056-3.
Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371(22):2141–2.
Siegal DM, Garcia D. Anticoagulants in cancer. J Thromb Haemost. 2012;10(11):2230–41.
Carrier M, Cameron C, Delluc A, Castellucci L, Khorana AA, Lee AY. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res. 2014;134(6):1214–9.
Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015;314(7):677–86.
Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146–53.
Lee AY, Peterson EA. Treatment of cancer-associated thrombosis. Blood. 2013;122(14):2310–7.
Posch F, Konigsbrugge O, Zielinski C, Pabinger I, Ay C. Treatment of venous thromboembolism in patients with cancer: a network meta-analysis comparing efficacy and safety of anticoagulants. Thromb Res. 2015;136(3):582–9.
NICE. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. London: National Institute for Health and Clinical Excellence; 2012.
Van Doormaal FF, Terpstra W, Van Der Griend R, Prins MH, Nijziel MR, Van De Ree MA, et al. Is extensive screening for cancer in idiopathic venous thromboembolism warranted? J Thromb Haemost. 2011;9(1):79–84.
Carrier M, Lazo-Langner A, Shivakumar S, Tagalakis V, Zarychanski R, Solymoss S, et al. Screening for occult cancer in unprovoked venous thromboembolism. N Engl J Med. 2015;373(8):697–704.
Galanaud JP, Sevestre MA, Genty C, Kahn SR, Pernod G, Rolland C, et al. Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis. J Thromb Haemost. 2014;12(4):436–43.
Palareti G, Schellong S. Isolated distal deep vein thrombosis: what we know and what we are doing. J Thromb Haemost. 2012;10(1):11–9.
Horner D, Hogg K, Body R. Should we be looking for and treating isolated calf vein thrombosis? Emerg Med J. 2015. doi:10.1136/emermed-2014-204230.
Palareti G. How I treat isolated distal deep vein thrombosis (IDDVT). Blood. 2014;123(12):1802–9.
Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315–52.
Decousus H, Bertoletti L, Frappe P. Spontaneous acute superficial vein thrombosis of the legs: do we really need to treat? J Thromb Haemost. 2015;13(Suppl 1):S230–7.
Decousus H, Prandoni P, Mismetti P, Bauersachs RM, Boda Z, Brenner B, et al. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med. 2010;363(13):1222–32.
Kasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser KD, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol. 1997;30(5):1165–71.
Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med. 2012;125(5):465–70.
Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311(23):2414–21.
Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033–73.
Meneveau N, Bassand JP, Schiele F, Bouras Y, Anguenot T, Bernard Y, et al. Safety of thrombolytic therapy in elderly patients with massive pulmonary embolism: a comparison with nonelderly patients. J Am Coll Cardiol. 1993;22(4):1075–9.
İpek G, Karataş MB, Onuk T, Güngör B, Yüzbaş B, Keskin M, et al. Effectiveness and safety of thrombolytic therapy in elderly patients with pulmonary embolism. J Thromb Thrombolysis. 2015;40(4):424–9.
Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402–11.
Gomez-Outes A, Lecumberri R, Suarez-Gea ML, Terleira-Fernandez AI, Monreal M, Vargas-Castrillon E. Case fatality rates of recurrent thromboembolism and bleeding in patients receiving direct oral anticoagulants for the initial and extended treatment of venous thromboembolism: a systematic review. J Cardiovasc Pharmacol Ther. 2015;20(5):490–500.
Sindet-Pedersen C, Pallisgaard JL, Olesen JB, Gislason GH, Arevalo LC. Safety and efficacy of direct oral anticoagulants compared to warfarin for extended treatment of venous thromboembolism -a systematic review and meta-analysis. Thromb Res. 2015;136(4):732–8.
Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999;340(12):901–7.
Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709–18.
Romualdi E, Donadini MP, Ageno W. Oral rivaroxaban after symptomatic venous thromboembolism: the continued treatment study (EINSTEIN-extension study). Expert Rev Cardiovasc Ther. 2011;9(7):841–4.
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699–708.
Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med. 2012;367(21):1979–87.
Becattini C, Agnelli G. Aspirin for prevention and treatment of venous thromboembolism. Blood Rev. 2014;28(3):103–8.
Simes J, Becattini C, Agnelli G, Eikelboom JW, Kirby AC, Mister R, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation. 2014;130(13):1062–71.
Imberti D, Dentali F, Ageno W, Crowther M, Garcia D, Huisman M, et al. Evidence and clinical judgment: vena cava filters. Thromb Haemost. 2014;111(4):618–24.
Mismetti P, Laporte S, Pellerin O, Ennezat PV, Couturaud F, Elias A, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015;313(16):1627–35.
Prins MH, Lensing AW, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, 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(1):21.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No external funding was used in the preparation of this manuscript.
Conflict of interest
Alexander Gallus has received honoraria from BMS/Pfizer for serving on the advisory boards of apixaban. Jir Ping Boey has no conflict of interest that might be relevant to the contents of this article.
Rights and permissions
About this article
Cite this article
Boey, J.P., Gallus, A. Drug Treatment of Venous Thromboembolism in the Elderly. Drugs Aging 33, 475–490 (2016). https://doi.org/10.1007/s40266-016-0378-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40266-016-0378-x