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Semin Thromb Hemost 2014; 40(06): 688-694
DOI: 10.1055/s-0034-1389083
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Anticoagulation in the Older Adult: Optimizing Benefit and Reducing Risk

Darae Ko
1   Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
,
Elaine M. Hylek
1   Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
› Author Affiliations
Further Information

Publication History

Publication Date:
03 September 2014 (online)

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Abstract

The risk for both arterial and venous thrombosis increases with age. Despite the increasing burden of strokes related to atrial fibrillation (AF) and venous thromboembolism (VTE) among older adults, the use of anticoagulant therapy is limited in this population due to the parallel increase in risk of serious hemorrhage. Understanding the risks and their underlying mechanisms would help to mitigate adverse events and improve persistence with these life-saving therapies. The objectives of this review are to: (1) elucidate the age-related physiologic changes that render this high risk subgroup susceptible to hemorrhage, (2) identify mutable risk factors and hazards contributing to an increased bleeding risk in older individuals, and (3) discuss interventions to optimize anticoagulation therapy in this population.

Keywords

aging - anticoagulation - warfarin - atrial fibrillation - stroke - venous thromboembolism
 

  • References

  • 1 Miyasaka Y, Barnes ME, Gersh BJ , et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114 (2) 119-125
    CrossrefPubMedGoogle Scholar
  • 2 Anderson Jr FA, Wheeler HB, Goldberg RJ , et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151 (5) 933-938
    CrossrefPubMedGoogle Scholar
  • 3 White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107 (23) (Suppl. 01) I4-I8
    PubMedGoogle Scholar
  • 4 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) 144-147
    PubMedGoogle Scholar
  • 5 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22 (8) 983-988
    CrossrefPubMedGoogle Scholar
  • 6 Cairns JA, Connolly SJ. Nonrheumatic atrial fibrillation. Risk of stroke and role of antithrombotic therapy. Circulation 1991; 84 (2) 469-481
    CrossrefPubMedGoogle Scholar
  • 7 Lin H-J, Wolf PA, Kelly-Hayes M , et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996; 27 (10) 1760-1764
    CrossrefPubMedGoogle Scholar
  • 8 Hylek EM, D'Antonio J, Evans-Molina C, Shea C, Henault LE, Regan S. Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37 (4) 1075-1080
    CrossrefPubMedGoogle Scholar
  • 9 Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011; 365 (21) 2002-2012
    CrossrefPubMedGoogle Scholar
  • 10 Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33 (12) 1500-1510
    CrossrefPubMedGoogle Scholar
  • 11 Gage BF, Yan Y, Milligan PE , et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006; 151 (3) 713-719
    CrossrefPubMedGoogle Scholar
  • 12 Fang MC, Chang Y, Hylek EM , et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141 (10) 745-752
    CrossrefPubMedGoogle Scholar
  • 13 Hart RG, Diener HC, Yang S , et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 2012; 43 (6) 1511-1517
    CrossrefPubMedGoogle Scholar
  • 14 Liao D, Cooper L, Cai J , et al. The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: the ARIC Study. Neuroepidemiology 1997; 16 (3) 149-162
    CrossrefPubMedGoogle Scholar
  • 15 Folsom AR, Yatsuya H, Mosley Jr TH, Psaty BM, Longstreth Jr WT. Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts. Ann Neurol 2012; 71 (4) 552-559
    CrossrefPubMedGoogle Scholar
  • 16 Smith EE, Rosand J, Knudsen KA, Hylek EM, Greenberg SM. Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke. Neurology 2002; 59 (2) 193-197
    CrossrefPubMedGoogle Scholar
  • 17 Caprio FZ, Maas MB, Rosenberg NF , et al. Leukoaraiosis on magnetic resonance imaging correlates with worse outcomes after spontaneous intracerebral hemorrhage. Stroke 2013; 44 (3) 642-646
    CrossrefPubMedGoogle Scholar
  • 18 Auriel E, Greenberg SM. The pathophysiology and clinical presentation of cerebral amyloid angiopathy. Curr Atheroscler Rep 2012; 14 (4) 343-350
    CrossrefPubMedGoogle Scholar
  • 19 Greenberg SM, Vonsattel J-PG. Diagnosis of cerebral amyloid angiopathy. Sensitivity and specificity of cortical biopsy. Stroke 1997; 28 (7) 1418-1422
    CrossrefPubMedGoogle Scholar
  • 20 Yates PA, Villemagne VL, Ellis KA, Desmond PM, Masters CL, Rowe CC. Cerebral microbleeds: a review of clinical, genetic, and neuroimaging associations. Front Neurol 2014; 4: 205
    PubMedGoogle Scholar
  • 21 Vernooij MW, van der Lugt A, Ikram MA , et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 2008; 70 (14) 1208-1214
    CrossrefPubMedGoogle Scholar
  • 22 Nighoghossian N, Hermier M, Adeleine P , et al. Old microbleeds are a potential risk factor for cerebral bleeding after ischemic stroke: a gradient-echo T2*-weighted brain MRI study. Stroke 2002; 33 (3) 735-742
    CrossrefPubMedGoogle Scholar
  • 23 Poels MM, Vernooij MW, Ikram MA , et al. Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke 2010; 41 (10, Suppl): S103-S106
    CrossrefPubMedGoogle Scholar
  • 24 Greenberg SM, Eng JA, Ning M, Smith EE, Rosand J. Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke 2004; 35 (6) 1415-1420
    CrossrefPubMedGoogle Scholar
  • 25 Yang AI, Balser DS, Mikheev A , et al. Cerebral atrophy is associated with development of chronic subdural haematoma. Brain Inj 2012; 26 (13-14) 1731-1736
    CrossrefPubMedGoogle Scholar
  • 26 Adhiyaman V, Asghar M, Ganeshram KN, Bhowmick BK. Chronic subdural haematoma in the elderly. Postgrad Med J 2002; 78 (916) 71-75
    CrossrefPubMedGoogle Scholar
  • 27 Yavorski RT, Wong RK, Maydonovitch C, Battin LS, Furnia A, Amundson DE. Analysis of 3,294 cases of upper gastrointestinal bleeding in military medical facilities. Am J Gastroenterol 1995; 90 (4) 568-573
    PubMedGoogle Scholar
  • 28 Rockall TA, Logan RF, Devlin HB, Northfield TC. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage. BMJ 1995; 311 (6999) 222-226
    CrossrefPubMedGoogle Scholar
  • 29 Yuan Y, Padol IT, Hunt RH. Peptic ulcer disease today. Nat Clin Pract Gastroenterol Hepatol 2006; 3 (2) 80-89
    PubMedGoogle Scholar
  • 30 Everhart JE, Kruszon-Moran D, Perez-Perez GI, Tralka TS, McQuillan G. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. J Infect Dis 2000; 181 (4) 1359-1363
    CrossrefPubMedGoogle Scholar
  • 31 Lim SH, Kwon JW, Kim N , et al. Prevalence and risk factors of Helicobacter pylori infection in Korea: nationwide multicenter study over 13 years. BMC Gastroenterol 2013; 13: 104
    CrossrefPubMedGoogle Scholar
  • 32 Bureš J, Kopáčová M, Koupil I , et al. Significant decrease in prevalence of Helicobacter pylori in the Czech Republic. World J Gastroenterol 2012; 18 (32) 4412-4418
    CrossrefPubMedGoogle Scholar
  • 33 Zhang M, Zhou YZ, Li XY , et al. Seroepidemiology of Helicobacter pylori infection in elderly people in the Beijing region, China. World J Gastroenterol 2014; 20 (13) 3635-3639
    CrossrefPubMedGoogle Scholar
  • 34 Huang J-Q, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002; 359 (9300) 14-22
    CrossrefPubMedGoogle Scholar
  • 35 Talley NJ, Evans JM, Fleming KC, Harmsen WS, Zinsmeister AR, Melton III LJ. Nonsteroidal antiinflammatory drugs and dyspepsia in the elderly. Dig Dis Sci 1995; 40 (6) 1345-1350
    CrossrefPubMedGoogle Scholar
  • 36 Lanas A, Bajador E, Serrano P , et al. Nitrovasodilators, low-dose aspirin, other nonsteroidal antiinflammatory drugs, and the risk of upper gastrointestinal bleeding. N Engl J Med 2000; 343 (12) 834-839
    CrossrefPubMedGoogle Scholar
  • 37 Farinati F, Formentini S, Della Libera G , et al. Changes in parietal and mucous cell mass in the gastric mucosa of normal subjects with age: a morphometric study. Gerontology 1993; 39 (3) 146-151
    CrossrefPubMedGoogle Scholar
  • 38 Hackelsberger A, Platzer U, Nilius M , et al. Age and Helicobacter pylori decrease gastric mucosal surface hydrophobicity independently. Gut 1998; 43 (4) 465-469
    CrossrefPubMedGoogle Scholar
  • 39 Lee M, Hardman WE, Cameron I. Age-related changes in gastric mucosal repair and proliferative activities in rats exposed acutely to aspirin. Gerontology 1998; 44 (4) 198-203
    CrossrefPubMedGoogle Scholar
  • 40 U.S. Food and Drug Administration. Use of aspirin for primary prevention of heart attack and stroke. Available at: http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm390574.htm . Accessed June 29, 2014
    PubMedGoogle Scholar
  • 41 Yachimski PS, Friedman LS. Gastrointestinal bleeding in the elderly. Nat Clin Pract Gastroenterol Hepatol 2008; 5 (2) 80-93
    CrossrefPubMedGoogle Scholar
  • 42 Longstreth GF. Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1997; 92 (3) 419-424
    PubMedGoogle Scholar
  • 43 Meyers MA, Alonso DR, Gray GF, Baer JW. Pathogenesis of bleeding colonic diverticulosis. Gastroenterology 1976; 71 (4) 577-583
    PubMedGoogle Scholar
  • 44 Peery AF, Barrett PR, Park D , et al. A high-fiber diet does not protect against asymptomatic diverticulosis. Gastroenterology 2012; 142 (2) 266-272, e1
    CrossrefPubMedGoogle Scholar
  • 45 Nagata N, Niikura R, Aoki T , et al. Colonic diverticular hemorrhage associated with the use of NSAIDs, low-dose aspirin, antiplatelet drugs, and dual therapy. J Gastroenterol Hepatol 2014; doi: 10.1111/jgh.12595
    PubMedGoogle Scholar
  • 46 Niikura R, Nagata N, Yamada A, Akiyama J, Shimbo T, Uemura N. Recurrence of colonic diverticular bleeding and associated risk factors. Colorectal Dis 2012; 14 (3) 302-305
    CrossrefPubMedGoogle Scholar
  • 47 Trifirò G, Spina E. Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab 2011; 12 (7) 611-620
    CrossrefPubMedGoogle Scholar
  • 48 Gurwitz JH, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med 1992; 116 (11) 901-904
    CrossrefPubMedGoogle Scholar
  • 49 James AH, Britt RP, Raskino CL, Thompson SG. Factors affecting the maintenance dose of warfarin. J Clin Pathol 1992; 45 (8) 704-706
    CrossrefPubMedGoogle Scholar
  • 50 Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 2005; 127 (6) 2049-2056
    CrossrefPubMedGoogle Scholar
  • 51 Shepherd AM, Hewick DS, Moreland TA, Stevenson IH. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol 1977; 4 (3) 315-320
    CrossrefPubMedGoogle Scholar
  • 52 Hämmerlein A, Derendorf H, Lowenthal DT. Pharmacokinetic and pharmacodynamic changes in the elderly. Clinical implications. Clin Pharmacokinet 1998; 35 (1) 49-64
    CrossrefPubMedGoogle Scholar
  • 53 Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 2003; 38 (8) 843-853
    CrossrefPubMedGoogle Scholar
  • 54 Durnas C, Loi CM, Cusack BJ. Hepatic drug metabolism and aging. Clin Pharmacokinet 1990; 19 (5) 359-389
    CrossrefPubMedGoogle Scholar
  • 55 James OF. Drugs and the ageing liver. J Hepatol 1985; 1 (4) 431-435
    CrossrefPubMedGoogle Scholar
  • 56 Vestal RE. Aging and determinants of hepatic drug clearance. Hepatology 1989; 9 (2) 331-334
    PubMedGoogle Scholar
  • 57 Woodhouse KW, Mutch E, Williams FM, Rawlins MD, James OFW. The effect of age on pathways of drug metabolism in human liver. Age Ageing 1984; 13 (6) 328-334
    CrossrefPubMedGoogle Scholar
  • 58 Grandison MK, Boudinot FD. Age-related changes in protein binding of drugs: implications for therapy. Clin Pharmacokinet 2000; 38 (3) 271-290
    CrossrefPubMedGoogle Scholar
  • 59 Le Couteur DG, McLean AJ. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet 1998; 34 (5) 359-373
    CrossrefPubMedGoogle Scholar
  • 60 Cogger VC, Hilmer SN, Svistounov D. Mechanisms and implications of age-related changes in the liver. Curr Gerontol Geriatr Res 2011; 2011: 150364
    PubMedGoogle Scholar
  • 61 Nwankwo T, Yoon SS, Burt V, Gu Q. Hypertension among adults in the United States: National Health and Nutrition Examination Survey, 2011-2012. NCHS Data Brief 2013; (133) 1-8
    PubMedGoogle Scholar
  • 62 Miura K. Epidemiology and prevention of hypertension in Japanese: how could Japan get longevity?. EPMA J 2011; 2 (1) 59-64
    CrossrefPubMedGoogle Scholar
  • 63 Murthy VL, Shah RV, Rubenfire M, Brook RD. Comparison of the Treatment Implications of American Society of Hypertension and International Society of Hypertension 2013 and Eighth Joint National Committee Guidelines: An Analysis of National Health and Nutrition Examination Survey. Hypertension 2014; 64: 275-280
    CrossrefPubMedGoogle Scholar
  • 64 Hylek EM, Ko D, Cove CL. Gaps in translation from trials to practice: non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation. Thromb Haemost 2014; 111 (5) 783-788
    Article in Thieme ConnectPubMedGoogle Scholar
  • 65 Johnson SG, Witt DM, Eddy TR, Delate T. Warfarin and antiplatelet combination use among commercially insured patients enrolled in an anticoagulation management service. Chest 2007; 131 (5) 1500-1507
    CrossrefPubMedGoogle Scholar
  • 66 Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 2003; 41 (4, Suppl S ): 62S-69S
    CrossrefPubMedGoogle Scholar
  • 67 Fiore LD, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi P. Combination Hemotherapy and Mortality Prevention (CHAMP) Study Group. Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study. Circulation 2002; 105 (5) 557-563
    CrossrefPubMedGoogle Scholar
  • 68 Flaker GC, Gruber M, Connolly SJ , et al; SPORTIF Investigators. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152 (5) 967-973
    CrossrefPubMedGoogle Scholar
  • 69 Hart RG, Benavente O, Pearce LA. Increased risk of intracranial hemorrhage when aspirin is combined with warfarin: A meta-analysis and hypothesis. Cerebrovasc Dis 1999; 9 (4) 215-217
    CrossrefPubMedGoogle Scholar
  • 70 Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ 2007; 177 (4) 347-351
    CrossrefPubMedGoogle Scholar
  • 71 You JJ, Singer DE, Howard PA , et al; American College of Chest Physicians. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e531S-e575S
    CrossrefPubMedGoogle Scholar
  • 72 Hylek EM, Go AS, Chang Y , et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349 (11) 1019-1026
    CrossrefPubMedGoogle Scholar
  • 73 Hylek EM, Regan S, Go AS, Hughes RA, Singer DE, Skates SJ. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med 2001; 135 (6) 393-400
    CrossrefPubMedGoogle Scholar
  • 74 Lopes RD, Horowitz JD, Garcia DA, Crowther MA, Hylek EM. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility. Blood 2011; 118 (24) 6269-6273
    CrossrefPubMedGoogle Scholar
  • 75 Sarani B, Temple-Lykens B, Kim P , et al. Factors associated with mortality and brain injury after falls from the standing position. J Trauma 2009; 67 (5) 954-958
    CrossrefPubMedGoogle Scholar
  • 76 Gage BF, Birman-Deych E, Kerzner R, Radford MJ, Nilasena DS, Rich MW. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005; 118 (6) 612-617
    CrossrefPubMedGoogle Scholar
  • 77 Bhatt DL, Scheiman J, Abraham NS , et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008; 118 (18) 1894-1909
    CrossrefPubMedGoogle Scholar
  • 78 Vallurupalli NG, Goldhaber SZ. Gastrointestinal complications of dual antiplatelet therapy. Circulation 2006; 113 (12) e655-e658
    CrossrefPubMedGoogle Scholar
  • 79 Berenson RA, Horvath J. Confronting the barriers to chronic care management in Medicare. Health Aff (Millwood) 2003; ;(Suppl Web Exclusives):W3-37 53
    PubMedGoogle Scholar
  • 80 Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 2002; 287 (3) 337-344
    Google Scholar
  • 81 Rochon PA. Drug prescribing for older adults. In: Schmader KE, Sokol HN, , eds. UpToDate. http://www.uptodate.com/contents/drug-prescribing-for-older-adults . Accessed June 1, 2014
    Google Scholar
  • 82 Bauersachs R, Berkowitz SD, Brenner B , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedGoogle Scholar
  • 83 Granger CB, Alexander JH, McMurray JJV , et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
    CrossrefPubMedGoogle Scholar
  • 84 Patel MR, Mahaffey KW, Garg J , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
    CrossrefPubMedGoogle Scholar
  • 85 Connolly SJ, Ezekowitz MD, Yusuf S , et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
    CrossrefPubMedGoogle Scholar
  • 86 Giugliano RP, Ruff CT, Braunwald E , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
    CrossrefPubMedGoogle Scholar
  • 87 Eikelboom JW, Wallentin L, Connolly SJ , 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 (21) 2363-2372
    CrossrefPubMedGoogle Scholar
  • 88 Halperin JL, Hankey GJ, Wojdyla DM , et al. ROCKET AF Steering Committee and Investigators*. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014; 130 (2) 138-146
    CrossrefPubMedGoogle Scholar
  • 89 Halvorsen S, Atar D, Yang H , et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 2014; 35 (28) 1864-1872
    CrossrefPubMedGoogle Scholar