Atrial Fibrillation and Stroke Prevention in Aging Patients
2014; Lippincott Williams & Wilkins; Volume: 130; Issue: 2 Linguagem: Inglês
10.1161/circulationaha.114.010873
ISSN1524-4539
AutoresJane E. Freedman, Bernard J. Gersh,
Tópico(s)Cardiac Arrhythmias and Treatments
ResumoHomeCirculationVol. 130, No. 2Atrial Fibrillation and Stroke Prevention in Aging Patients Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAtrial Fibrillation and Stroke Prevention in Aging PatientsWhat's Good Can be Even Better Jane E. Freedman, MD and Bernard J. Gersh, MB, ChB, DPhil, FRCP Jane E. FreedmanJane E. Freedman From the Division of Cardiology, University of Massachusetts Medical School, Worcester, MA (J.E.F.); and the Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN (B.J.G.). and Bernard J. GershBernard J. Gersh From the Division of Cardiology, University of Massachusetts Medical School, Worcester, MA (J.E.F.); and the Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, Rochester, MN (B.J.G.). Originally published3 Jun 2014https://doi.org/10.1161/CIRCULATIONAHA.114.010873Circulation. 2014;130:129–131Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 8, 2014: Previous Version 1 The most common arrhythmia in older adults is atrial fibrillation, with an estimated prevalence of ≈9% in adults aged ≥80 years and a concomitant increased burden of developing stroke. Additionally, over the past decade, both the incidence and prevalence of atrial fibrillation has markedly increased1 and, with it, the total number of patients potentially requiring long-term oral anticoagulation therapy for the prevention of stroke and systemic embolism. In 2009, the estimated number of atrial fibrillation diagnoses in the United States was 2 643 000, with equal distribution between men and women and 82% at ages ≥65 years, with that number increasing 10% between 1999 to 2005.2 The magnitude of the problem is exemplified by the fact that the risk of stroke in patients with atrial fibrillation increases with age and accounts for ≈45% of embolic strokes, approximately 100 000 annually in the United States.3Article see p 138The advent of the novel oral anticoagulants has strikingly shifted the goalposts in the field of stroke prevention. Large randomized trials of 4 agents involving 71 683 participants4 have demonstrated that these drugs are at least noninferior to warfarin for the prevention of stroke and systemic embolism and, in the case of apixiban and higher doses of dabigatran, the trials demonstrated superiority over warfarin. In addition, these agents have demonstrated a consistent and striking impact on reducing intracerebral hemorrhage and major bleeding. Moreover, a recent meta-analysis demonstrated an overall reduction in mortality of ≈10%.4A major issue in these studies is the increased bleeding and stroke rates in select populations. Among patients with atrial fibrillation treated with anticoagulation, the risk was found to be higher among Asians, blacks, and the elderly.5 Complicating the treatment for atrial fibrillation in the aging population is a higher risk of bleeding. This is another example of what we find often in medicine; namely, the greater the potential benefit the greater the risk. In the case of atrial fibrillation, this is easily accounted for by the fact that many of the components of risk stratification scores for stroke are also incorporated into the algorithm used to predict the risk of bleeding. This requires careful consideration to ensure both efficient and safe oral anticoagulation and, in the case of the novel oral anticoagulants, it is imperative that protocols be put into place to optimize their use in multiple situations (eg, renal dysfunction, during procedures, following a bleeding episode) and using metrics to determine how to measure their effect. In addition, anticoagulants are widely underutilized in the community in general and, in particular, among the elderly. It appears that physicians are more concerned about bleeding in contrast to patients in whom the major fear is that of stroke.6,7 To compound the problem further, even among patients prescribed anticoagulants, there is a high rate of discontinuation. In the setting of cardiovascular disease, most elderly with atrial fibrillation who undergo percutaneous coronary intervention with stent placement receive dual rather than triple therapy at discharge.8Addressing the problem of atrial fibrillation in the aging population is a study by Halperin et al9 in the current issue of Circulation. To examine atrial fibrillation in the elderly, this group utilized the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial using a prespecified secondary analysis comparing outcomes in patients aged >75 years with younger patients. The ROCKET AF trial, a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, initially showed that this new oral factor Xa inhibitor was noninferior to warfarin.10 In the current analyses, there were 6229 patients aged >75 years with AF and >2 stroke risk factors who were randomized to warfarin or rivaroxaban. The primary end point was all strokes (ischemic or hemorrhagic) and systemic embolism according to intention to treat. They found that older participants had higher rates of primary events (2.57% vs. 2.05%/100 pt-yrs, and major bleeding (4.63% versus 2.74%/100 pt-yrs). Hemorrhagic stroke rates in patients aged >75 years were similar to younger patients with no interaction between age and response to rivaroxaban. The conclusion was, as expected, older patients with atrial fibrillation have higher rates of stroke, embolic events, and major bleeding, but the relative efficacy and safety of rivaroxaban compared with warfarin did not differ with age.In general terms, these findings are consistent with benefit seen in previous subgroup analyses including the demonstration that, in patients with peripheral arterial disease in ROCKET AF, there was no statistically significant higher risk of stroke or systemic embolism and there was similar efficacy outcomes in patients treated with rivaroxaban and warfarin.11 These findings are also consistent with observations seen with other newer oral anticoagulants. The benefits of apixaban versus warfarin have been shown to be consistent in patients with atrial fibrillation regardless of age. In fact, adjusting for the higher risk at older age, the absolute benefits of apixaban were reported greater in the elderly.12In addition to potentially offering benefit in terms of bleeding risk, newer oral anticoagulants may offer increased convenience for elderly patients, because of their more predictable pharmacologic profiles, a rapid onset of action, a broader therapeutic window, and no specific requirement for routine coagulation monitoring. Also, these therapies have far fewer food and drug interactions as compared with warfarin.13The question remains, even if reassured that the use of new oral anticoagulants is, at least, noninferior in terms of risk/benefit, can we do better? Already, anticoagulants are recommended in patients with atrial fibrillation aged ≥75 years after assessing the bleeding risk using the HEMORR2HAGES or HAS-BLED scores.14 Some suggest HAS-BLED has better predictive value in the elderly.15 However, can these scores be improved on to assist with their use in the older patient? In the elderly, newer oral anticoagulants, all of which are renally excreted to a variable extent, should take into account renal function as well as and cognitive function specifically for adherence to treatment.16 It should be emphasized that renal function is a dynamic entity that requires frequent re-assessment. Furthermore, all but 1 of the 4 anticoagulants are prescribed twice daily and, given their shorter half-lives, compliance is a critical issue. Additional therapies including antiarrhythmic drugs should be used cautiously in elderly patients because of the frequency of metabolic abnormalities and higher risk of drug interactions.Is there still a role for warfarin? Warfarin remains the drug of choice in patients with mechanical valves, left ventricular thrombi, rheumatic mitral valve disease, and severe renal dysfunction. In patients on warfarin with a stable INR and easy access to an anticoagulation clinic or among whom home INR testing has been effective, there is certainly no compelling rationale for switching to a newer oral anticoagulant. In patients in whom compliance is an issue, the ability to check the INR is helpful. This is also the case in patients at a higher risk of bleeding in whom INR monitoring to maintain a goal in the low therapeutic range is a reasonable option. It is also possible that newer medications such as Tercarferin, an orally active Vitamin K epoxide inhibitor, will have a role in select settings such as in valvular disease. Finally, cost will remain an issue for many, especially the elderly.Although more recent fundamental biological, diagnostic, and therapeutic developments raise hope that atrial fibrillation or the resulting stroke can be prevented or mitigated, many gaps do and will remain and likely will include older adults with a myriad of risks and medications. Thus, the public health importance of atrial fibrillation and stroke in elderly adults remains strong and should direct areas for investigation that may mitigate stroke-related morbidity. Clearly needed are innovative approaches that may ultimately facilitate the application of novel preventive, diagnostic, and therapeutic insights into the management of older adults with atrial fibrillation.17Nonetheless, the search for new approaches should not divert attention away from improving on what is already in place. First, the gap between those eligible for oral anticoagulants and those receiving these drugs must be closed. Second, it should also be emphasized that the data supporting aspirin as an alternative to warfarin are not strong and the recent European Society of Cardiology guidelines do not identify any role for aspirin in stroke prevention in atrial fibrillation. Aspirin may be a major contributor to bleeding in patients already on warfarin and in the elderly; in particular, the reasons for concomitant aspirin therapy need to be carefully evaluated.18 Third, we should appreciate that the majority of atrial fibrillation cases may be the consequence of risk factors causing increased arterial stiffness, diastolic dysfunction, and atrial volume overload.19 Thus, it may be prudent to aim for aggressive risk factor modification as an intrinsic aspect in the management of atrial fibrillation.20In summary, in this issue of Circulation, Halperin and colleagues,9 using data from the ROCKET AF trial, demonstrate the utility of using rivaroxaban in older adults. Regardless of the medication chosen, however, older patients must always be treated cautiously because of an increased risk of stroke and bleeding, and additional challenges related to drug interactions. Despite the higher risk of primary events as well as risk attributable to the medications themselves, newer oral anticoagulants may be suitable alternatives to warfarin in older patients as a result of specific advantages: no need for regular monitoring, more rapid onset of action, and fewer drug and food interactions. As additional data are gathered in this large and higher risk population, our ability to guide optimal use in terms of risk/benefit, as well as choose the optimal medication/dosage and mitigate drug interaction, will expand and lead to better care of our older patients. However, although there is no doubt about the benefits of oral anticoagulation in the elderly, focus must be placed on reducing their risk.Sources of FundingDr Freedman is supported by RFA-HL-12-008 and RFA-RM-12-013NIH from Common Fund, through the Office of Strategic Coordination/Office of the National Institutes of Health Director.DisclosuresDr Gersh is a consultant for Ortho-McNeill Jansen Pharmaceuticals. Dr Freedman reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Jane E. Freedman, MD, UMass Memorial Heart & Vascular Center, AS7-1051, 368 Plantation St, Worcester, MA 01605-4319. E-mail [email protected]References1. Miyasaka Y, Barnes ME, Bailey KR, Cha SS, Gersh BJ, Seward JB, Tsang TS. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study.J Am Coll Cardiol. 2007; 49:986–992.CrossrefMedlineGoogle Scholar2. Arowolaju A, Gillum RF. A new decline in hospitalization with atrial fibrillation among the elderly.Am J Med. 2013; 126:455–457.CrossrefMedlineGoogle Scholar3. Braunwald E. Shattuck lecture–cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities.N Engl J Med. 1997; 337:1360–1369.CrossrefMedlineGoogle Scholar4. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.Lancet. 2014; 383:955–962.CrossrefMedlineGoogle Scholar5. Hankey GJ, Stevens SR, Piccini JP, Lokhnygina Y, Mahaffey KW, Halperin JL, Patel MR, Breithardt G, Singer DE, Becker RC, Berkowitz SD, Paolini JF, Nessel CC, Hacke W, Fox KA, Califf RM. Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: The rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation.Stroke. 2014; 45:1304–1312.LinkGoogle Scholar6. Devereaux PJ, Anderson DR, Gardner MJ, Putnam W, Flowerdew GJ, Brownell BF, Nagpal S, Cox JL. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study.BMJ. 2001; 323:1218–1222.CrossrefMedlineGoogle Scholar7. Cowan C, Healicon R, Robson I, Long WR, Barrett J, Fay M, Tyndall K, Gale CP. The use of anticoagulants in the management of atrial fibrillation among general practices in England.Heart. 2013; 99:1166–1172.CrossrefMedlineGoogle Scholar8. Fosbol EL, Wang TY, Li S, Piccini J, Lopes RD, Mills RM, Klaskala W, Thomas L, Roe MT, Peterson ED. Warfarin use among older atrial fibrillation patients with non-ST-segment elevation myocardial infarction managed with coronary stenting and dual antiplatelet therapy.Am Heart J. 2013; 166:864–870.CrossrefMedlineGoogle Scholar9. Halperin JL, Hankey GJ, Wojdyla DM, Piccini JP, Lokhnygina Y, Patel MR, Breithardt G, Singer DE, Becker RC, Hacke W, Paolini JF, Nessel CC, Mahaffey KW, Califf RM, Fox KAA. 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; 130:138–146.LinkGoogle Scholar10. Sherwood MW, Douketis JD, Patel MR, Piccini JP, Hellkamp AS, Lokhnygina Y, Spyropoulos AC, Hankey GJ, Singer DE, Nessel CC, Mahaffey KW, Fox KA, Califf RM, Becker RC. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: Results from ROCKET AF.Circulation. 2014; 129:1850–1859. doi: 10.1161/CIRCULATIONAHA.113.005754. Epub 2014 Feb 19.LinkGoogle Scholar11. Jones WS, Hellkamp AS, Halperin J, Piccini JP, Breithardt G, Singer DE, Fox KA, Hankey GJ, Mahaffey KW, Califf RM, Patel MR. Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF.Eur Heart J. 2014; 35:242–249.CrossrefMedlineGoogle Scholar12. Halvorsen S, Atar D, Yang H, De Caterina R, Erol C, Garcia D, Granger CB, Hanna M, Held C, Husted S, Hylek EM, Jansky P, Lopes RD, Ruzyllo W, Thomas L, Wallentin L. 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 Feb 20. [Epub ahead of print].CrossrefGoogle Scholar13. Deedwania PC. New oral anticoagulants in elderly patients with atrial fibrillation.Am J Med. 2013; 126:289–296.CrossrefMedlineGoogle Scholar14. Roldán V, Marín F, Fernández H, Manzano-Fernandez S, Gallego P, Valdés M, Vicente V, Lip GY. Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a "real-world" population with atrial fibrillation receiving anticoagulant therapy.Chest. 2013; 143:179–184.CrossrefMedlineGoogle Scholar15. Roldán V, Marín F, Manzano-Fernández S, Gallego P, Vílchez JA, Valdés M, Vicente V, Lip GY. The HAS-BLED score has better prediction accuracy for major bleeding than CHADS2 or CHA2DS2-VASc scores in anticoagulated patients with atrial fibrillation.J Am Coll Cardiol. 2013; 62:2199–2204.CrossrefMedlineGoogle Scholar16. Lip GY. Stroke and bleeding risk assessment in atrial fibrillation: when, how, and why?Eur Heart J. 2013; 34:1041–1049.CrossrefMedlineGoogle Scholar17. Lubitz SA, Bauer KA, Benjamin EJ, Besdine RW, Forman DE, Gurol ME, Reddy VY, Singer DE. Stroke prevention in atrial fibrillation in older adults: existing knowledge gaps and areas for innovation: a summary of an American Federation for Aging research seminar.J Am Geriatr Soc. 2013; 61:1798–1803.CrossrefMedlineGoogle Scholar18. Steinberg BA, Kim S, Piccini JP, Fonarow GC, Lopes RD, Thomas L, Ezekowitz MD, Ansell J, Kowey P, Singer DE, Gersh B, Mahaffey KW, Hylek E, Go AS, Chang P, Peterson ED; ORBIT-AF Investigators and Patients. Use and associated risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry.Circulation. 2013; 128:721–728.LinkGoogle Scholar19. Tsang TS, Gersh BJ, Appleton CP, Tajik AJ, Barnes ME, Bailey KR, Oh JK, Leibson C, Montgomery SC, Seward JB. Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women.J Am Coll Cardiol. 2002; 40:1636–1644.CrossrefMedlineGoogle Scholar20. Abed HS, Wittert GA, Leong DP, Shirazi MG, Bahrami B, Middeldorp ME, Lorimer MF, Lau DH, Antic NA, Brooks AG, Abhayaratna WP, Kalman JM, Sanders P. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial.JAMA. 2013; 310:2050–2060.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Gorczyca-Głowacka I, Bielecka B, Wałek P, Chrapek M, Ciba-Stemplewska A, Jelonek O, Kot A, Czyżyk A, Pióro M, Major A and Wożakowska-Kapłon B (2022) Temporal Trends in Oral Anticoagulant Prescription in Atrial Fibrillation Patients between 2004 and 2019, International Journal of Environmental Research and Public Health, 10.3390/ijerph19095584, 19:9, (5584) Tapaskar N, Ham S, Micic D and Sengupta N (2022) Restarting Warfarin vs Direct Oral Anticoagulants After Major Gastrointestinal Bleeding and Associated Outcomes in Atrial Fibrillation: A Cohort Study, Clinical Gastroenterology and Hepatology, 10.1016/j.cgh.2020.11.029, 20:2, (381-389.e9), Online publication date: 1-Feb-2022. Szpotowicz A, Gorczyca I, Jelonek O, Uziębło-Życzkowska B, Maciorowska M, Wójcik M, Błaszczyk R, Kapłon-Cieślicka A, Gawałko M, Budnik M, Tokarek T, Rajtar-Salwa R, Bil J, Wojewódzki M, Bednarski J, Bakuła-Ostalska E, Tomaszuk-Kazberuk A, Szyszkowska A, Wełnicki M, Mamcarz A, Krzciuk M and Wożakowska-Kapłon B (2021) Why Did All Patients with Atrial Fibrillation and High Risk of Stroke Not Receive Oral Anticoagulants? Results of the Polish Atrial Fibrillation (POL-AF) Registry, Journal of Clinical Medicine, 10.3390/jcm10194611, 10:19, (4611) Sanjoy S, Choi Y, Sparrow R, Jneid H, Dawn Abbott J, Nombela‐Franco L, Azzalini L, Holmes D, Alraies M, Elgendy I, Baranchuk A, Mamas M and Bagur R (2021) Outcomes of Elderly Patients Undergoing Left Atrial Appendage Closure, Journal of the American Heart Association, 10:19, Online publication date: 5-Oct-2021. Gorczyca I, Jelonek O, Michalska A, Chrapek M, Wałek P and Wożakowska-Kapłon B (2020) Stroke prevention and guideline adherent antithrombotic treatment in elderly patients with atrial fibrillation, Medicine, 10.1097/MD.0000000000021209, 99:29, (e21209) Buccheri S, Angiolillo D and Capodanno D (2019) Evolving paradigms in antithrombotic therapy for anticoagulated patients undergoing coronary stenting, Therapeutic Advances in Cardiovascular Disease, 10.1177/1753944719891688, 13, (175394471989168), Online publication date: 1-Jan-2019. Suárez Fernández C, Mostaza J, Castilla Guerra L, Cantero Hinojosa J, Suriñach J, Acosta de Bilbao F, Tamarit J, Diaz Diaz J, Hernandez J, Cazorla D and Ràfols C (2018) Seguimiento de las recomendaciones del Informe de Posicionamiento Terapéutico sobre el tratamiento con anticoagulantes orales en pacientes ancianos con fibrilación auricular. Estudio ESPARTA, Medicina Clínica, 10.1016/j.medcli.2017.07.025, 151:1, (8-15), Online publication date: 1-Jul-2018. Suárez Fernández C, Mostaza J, Castilla Guerra L, Cantero Hinojosa J, Suriñach J, Acosta de Bilbao F, Tamarit J, Diaz Diaz J, Hernandez J, Cazorla D and Ràfols C (2018) Adherence to recommendations of the Therapeutic Positioning Report about treatment with oral anticoagulants in elderly patients with atrial fibrillation. The ESPARTA study, Medicina Clínica (English Edition), 10.1016/j.medcle.2018.05.002, 151:1, (8-15), Online publication date: 1-Jul-2018. Nagaratnam N, Nagaratnam K and Cheuk G (2018) Primary and Secondary Prevention of Stroke Geriatric Diseases, 10.1007/978-3-319-33434-9_78, (715-723), . Alamneh E, Chalmers L and Bereznicki L (2017) The Tasmanian atrial fibrillation study: Transition to direct oral anticoagulants 2011-2015, Cardiovascular Therapeutics, 10.1111/1755-5922.12254, 35:3, (e12254), Online publication date: 1-Jun-2017. Nagaratnam N, Nagaratnam K and Cheuk G (2017) Primary and Secondary Prevention of Stroke Geriatric Diseases, 10.1007/978-3-319-32700-6_78-1, (1-9), . Sarvari S, Haugaa K, Stokke T, Ansari H, Leren I, Hegbom F, Smiseth O and Edvardsen T (2015) Strain echocardiographic assessment of left atrial function predicts recurrence of atrial fibrillation, European Heart Journal – Cardiovascular Imaging, 10.1093/ehjci/jev185, 17:6, (660-667), Online publication date: 1-Jun-2016. Alamneh E, Chalmers L and Bereznicki L (2016) Suboptimal Use of Oral Anticoagulants in Atrial Fibrillation: Has the Introduction of Direct Oral Anticoagulants Improved Prescribing Practices?, American Journal of Cardiovascular Drugs, 10.1007/s40256-016-0161-8, 16:3, (183-200), Online publication date: 1-Jun-2016. Suárez Fernández C, Camafort M, Cepeda Rodrigo J, Díez-Manglano J, Formiga F, Pose Reino A, Tiberio G and Mostaza J (2015) Antithrombotic treatment in elderly patients with atrial fibrillation, Revista Clínica Española (English Edition), 10.1016/j.rceng.2014.11.005, 215:3, (171-181), Online publication date: 1-Apr-2015. Suárez Fernández C, Camafort M, Cepeda Rodrigo J, Díez-Manglano J, Formiga F, Pose Reino A, Tiberio G and Mostaza J (2015) Tratamiento antitrombótico en el paciente anciano con fibrilación auricular, Revista Clínica Española, 10.1016/j.rce.2014.11.024, 215:3, (171-181), Online publication date: 1-Apr-2015. Yates S and Sarode R (2014) Reversal of Anticoagulant Effects in Patients with Intracerebral Hemorrhage, Current Neurology and Neuroscience Reports, 10.1007/s11910-014-0504-2, 15:1, Online publication date: 1-Jan-2015. July 8, 2014Vol 130, Issue 2 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.114.010873PMID: 24895453 Originally publishedJune 3, 2014 KeywordsagingstrokeEditorialsarrhythmiaanticoagulantPDF download Advertisement SubjectsAnticoagulantsCerebrovascular Disease/StrokeIntracranial HemorrhagePrimary Prevention
Referência(s)