Cardioembolic stroke: Practical considerations for patient risk management and secondary prevention

Postgraduate Medicine

Volumn 126, Issue 1, 2014, Pages 55-65

  Amin, Hardik ^a   Nowak, Richard J ^a   Schindler, Joseph L ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cardioembolic stroke; Etiology; Risk management; Secondary prevention

Indexed keywords

ACETYLSALICYLIC ACID; ANTICOAGULANT AGENT; ANTITHROMBOCYTIC AGENT; APIXABAN; CLOPIDOGREL; DABIGATRAN; HEPARIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IRBESARTAN; RIVAROXABAN; WARFARIN;

AORTA ATHEROSCLEROSIS; ARTICLE; ATRIAL FIBRILLATION; BRAIN HEMORRHAGE; CARDIOEMBOLIC STROKE; CATHETER ABLATION; CONGENITAL HEART DISEASE; DIABETES MELLITUS; HEART ARRHYTHMIA; HEART EJECTION FRACTION; HEART FAILURE; HEART INFARCTION; HEART LEFT VENTRICLE FAILURE; HUMAN; HYPERTENSION; PATENT FORAMEN OVALE; RANDOMIZED CONTROLLED TRIAL (TOPIC); RISK FACTOR; TRANSTHORACIC ECHOCARDIOGRAPHY; VALVULAR HEART DISEASE; CARDIOVASCULAR DISEASE; CEREBROVASCULAR ACCIDENT; ELECTROCARDIOGRAPHY; INTERNATIONAL NORMALIZED RATIO; METHODOLOGY; REVIEW; RISK MANAGEMENT; SECONDARY PREVENTION; THROMBOEMBOLISM; TRANSESOPHAGEAL ECHOCARDIOGRAPHY;

ANTICOAGULANTS; CARDIOVASCULAR DISEASES; ECHOCARDIOGRAPHY, TRANSESOPHAGEAL; ELECTROCARDIOGRAPHY; HUMANS; INTERNATIONAL NORMALIZED RATIO; RISK MANAGEMENT; SECONDARY PREVENTION; STROKE; THROMBOEMBOLISM;

EID: 84897018174     PISSN: 00325481     EISSN: 19419260     Source Type: Journal    
DOI: 10.3810/pgm.2014.01.2725     Document Type: Article

References (102)

1. Sandercock PA, Warlow CP, Jones LN, Starkey IR. Predisposing factors for cerebral infarction: the Oxfordshire community stroke project. BMJ. 1989;298(6666):75–80.
2. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2011;42(1):227–276.
3. Bogousslavsky J, Cachin C, Regli F, Despland PA, Van Melle G, Kappenberger L. Cardiac sources of embolism and cerebral infarction- -clinical consequences and vascular concomitants: the Lausanne Stroke Registry. Neurology. 1991;41(6):855–859.
4. Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke. 2001;32(10):2333–2337.
5. Cheitlin MD, Armstrong WF, Aurigemma GP, et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). Circulation. 2003;108(9):1146–1162.
6. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol. 1991;17(1):66–72.
7. Harloff A, Handke M, Reinhard M, Geibel A, Hetzel A. Therapeutic strategies after examination by transesophageal echocardiography in 503 patients with ischemic stroke. Stroke. 2006;37(3):859–864.
8. DeRook FA, Comess KA, Albers GW, Popp RL. Transesophageal echocardiography in the evaluation of stroke. Ann Intern Med. 1992;117(11):922–932.
9. 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.
10. Wolf PA, Kannel WB, McGee DL, Meeks SL, Bharucha NE, McNamara PM. Duration of atrial fibrillation and imminence of stroke: the Framingham study. Stroke. 1983;14(5):664–667.
11. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke. 2001;32(12):2735–2740.
12. Arboix A, García-Eroles L, Massons J, Oliveres M. Predictive clinical factors of in-hospital mortality in 231 consecutive patients with cardioembolic cerebral infarction. Cerebrovasc Dis. 1998;8(1):8–13.
13. Eriksson SE, Olsson JE. Survival and recurrent strokes in patients with different subtypes of stroke: a fourteen-year follow-up study. Cerebrovasc Dis. 2001;12(3):171–180.
14. Lazzaro MA, Krishnan K, Prabhakaran S. Detection of atrial fibrillation with concurrent holter monitoring and continuous cardiac telemetry following ischemic stroke and transient ischemic attack. J Stroke Cerebrovasc Dis. 2012;21(2):89–93.
15. Jabaudon D, Sztajzel J, Sievert K, Landis T, Sztajzel R. Usefulness of ambulatory 7-day ECG monitoring for the detection of atrial fibrillation and flutter after acute stroke and transient ischemic attack. Stroke. 2004;35(7):1647–1651.
16. Tayal AH, Tian M, Kelly KM, et al. Atrial fibrillation detected by mobile cardiac outpatient telemetry in cryptogenic TIA or stroke. Neurology. 2008;71(21):1696–1701.
17. Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation. 2004;110(16):2287–2292.
18. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864–2870.
19. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257–e354.
20. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M, Committee CAFG. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol. 2011;27(1):74–90.
21. European Heart Rhythm Association; European Association for Cardio- Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19):2369–2429.
22. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263–272.
23. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857–867.
24. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996;348(9028):633–638.
25. White HD, Gruber M, Feyzi J, 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(3):239–245.
26. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360(20):2066–2078.
27. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151.
28. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992.
29. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891.
30. Pradaxa [product monograph]; 2010. www.boehringer-ingelheim.ca. Accessed December 12, 2012.
31. Xarelto [package insert]; 2012. http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf#zoom=100. Accessed December 12, 2012.
32. ELIQUIS [product monograph]; 2012. http://www.pfizer.ca/en/our_products/products/monograph/313. Accessed December 12, 2012.
33. Chen S, Dong Y, Fan J, Yin Y. Rate vs. rhythm control in patients with atrial fibrillation - an updated meta-analysis of 10 randomized controlled trials. Int J Cardiol. 2011;153(1):96–98.
34. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Heart Rhythm. 2011;8(1):157–176.
35. Edgerton ZJ, Edgerton JR. A review of current surgical treatment of patients with atrial fibrillation. Proc (Bayl Univ Med Cent). 2012;25(3):218–223.
36. Salem DN, Daudelin HD, Levine HJ, Pauker SG, Eckman MH, Riff J. Antithrombotic therapy in valvular heart disease. Chest. 2001;119(1 Suppl):207S–219S.
37. Wood P. Diseases of the Heart and Circulation. Philadelpia, PA: Lippincott; 1956.
38. Ellis LB, Harken DE. Arterial embolization in relation to mitral valvuloplasty. Am Heart J. 1961;62:611–620.
39. Szekely P. Systemic embolism and anticoagulant prophylaxis in rheumatic heart disease. Br Med J. 1964;1(5392):1209–1212.
40. Deverall PB, Olley PM, Smith DR, Watson DA, Whitaker W. Incidence of systemic embolism before and after mitral valvotomy. Thorax. 1968;23(5):530–536.
41. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;52(13):e1–e142.
42. Benjamin EJ, Plehn JF, D’Agostino RB, et al. Mitral annular calcification and the risk of stroke in an elderly cohort. N Engl J Med. 1992;327(6):374–379.
43. Savage DD, Garrison RJ, Castelli WP, et al. Prevalence of submitral (anular) calcium and its correlates in a general population-based sample (the Framingham Study). Am J Cardiol. 1983;51(8):1375–1378.
44. Fulkerson PK, Beaver BM, Auseon JC, Graber HL. Calcification of the mitral annulus: etiology, clinical associations, complications and therapy. Am J Med. 1979;66(6):967–977.
45. Nestico PF, Depace NL, Morganroth J, Kotler MN, Ross J. Mitral annular calcification: clinical, pathophysiology, and echocardiographic review. Am Heart J. 1984;107(5 Pt 1):989–996.
46. Kirk RS, Russell JG. Subvalvular calcification of mitral valve. Br Heart J. 1969;31(6):684–692.
47. Ridolfi RL, Hutchins GM. Spontaneous calcific emboli from calcific mitral annulus fibrosus. Arch Pathol Lab Med. 1976;100(3):117–120.
48. Brockmeier LB, Adolph RJ, Gustin BW, Holmes JC, Sacks JG. Calcium emboli to the retinal artery in calcific aortic stenosis. Am Heart J. 1981;101(1):32–37.
49. Stein PD, Sabbah HN, Pitha JV. Continuing disease process of calcific aortic stenosis. Role of microthrombi and turbulent flow. Am J Cardiol. 1977;39(2):159–163.
50. Edmunds LH. Thrombotic and bleeding complications of prosthetic heart valves. Ann Thorac Surg. 1987;44(4):430–445.
51. Vongpatanasin W, Hillis LD, Lange RA. Prosthetic heart valves. N Engl J Med. 1996;335(6):407–416.
52. Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation. 1994;89(2):635–641.
53. Kulik A, Rubens FD, Wells PS, et al. Early postoperative anticoagulation after mechanical valve replacement: a systematic review. Ann Thorac Surg. 2006;81(2):770–781.
54. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH, Physicians ACoC. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e576S–600S.
55. Singhal AB, Topcuoglu MA, Buonanno FS. Acute ischemic stroke patterns in infective and nonbacterial thrombotic endocarditis: a diffusion-weighted magnetic resonance imaging study. Stroke. 2002;33(5):1267–1273.
56. Kanter MC, Hart RG. Neurologic complications of infective endocarditis. Neurology. 1991;41(7):1015–1020.
57. Bamford J, Hodges J, Warlow C. Late rupture of a mycotic aneurysm after “cure” of bacterial endocarditis. J Neurol. 1986;233(1):51–53.
58. Tornos P, Almirante B, Mirabet S, Permanyer G, Pahissa A, Soler-Soler J. Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy. Arch Intern Med. 1999;159(5):473–475.
59. Di Tullio MR, Sacco RL, Savoia MT, Sciacca RR, Homma S. Aortic atheroma morphology and the risk of ischemic stroke in a multiethnic population. Am Heart J. 2000;139(2 Pt 1):329–336.
60. Stone DA, Hawke MW, LaMonte M, et al. Ulcerated atherosclerotic plaques in the thoracic aorta are associated with cryptogenic stroke: a multiplane transesophageal echocardiographic study. Am Heart J. 1995;130(1):105–108.
61. Amarenco P, Duyckaerts C, Tzourio C, Hénin D, Bousser MG, Hauw JJ. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med. 1992;326(4):221–225.
62. Tunick PA, Kronzon I. Protruding atherosclerotic plaque in the aortic arch of patients with systemic embolization: a new finding seen by transesophageal echocardiography. Am Heart J. 1990;120(3):658–660.
63. Amarenco P, Cohen A, Baudrimont M, Bousser MG. Transesophageal echocardiographic detection of aortic arch disease in patients with cerebral infarction. Stroke. 1992;23(7):1005–1009.
64. Harloff A, Strecker C, Dudler P, et al. Retrograde embolism from the descending aorta: visualization by multidirectional 3D velocity mapping in cryptogenic stroke. Stroke. 2009;40(4):1505–1508.
65. Lima JA, Desai MY, Steen H, Warren WP, Gautam S, Lai S. Statininduced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation. 2004;110(16):2336–2341.
66. Meier B, Frank B, Wahl A, Diener HC. Secondary stroke prevention: patent foramen ovale, aortic plaque, and carotid stenosis. Eur Heart J. 2012;33(6):705–713, 713a, 713b.
67. Witt BJ, Ballman KV, Brown RD, Meverden RA, Jacobsen SJ, Roger VL. The incidence of stroke after myocardial infarction: a meta-analysis. Am J Med. 2006;119(4):354, e351–359.
68. Fuster V, Halperin JL. Left ventricular thrombi and cerebral embolism. N Engl J Med. 1989;320(6):392–394.
69. Cardiogenic brain embolism. The second report of the Cerebral Embolism Task Force. Arch Neurol. 1989;46(7):727–743.
70. Natarajan D, Hotchandani RK, Nigam PD. Reduced incidence of left ventricular thrombi with intravenous streptokinase in acute anterior myocardial infarction: prospective evaluation by cross-sectional echocardiography. Int J Cardiol. 1988;20(2):201–207.
71. Visser CA, Kan G, Meltzer RS, Lie KI, Durrer D. Long-term followup of left ventricular thrombus after acute myocardial infarction. A two-dimensional echocardiographic study in 96 patients. Chest. 1984;86(4):532–536.
72. Pullicino PM, Halperin JL, Thompson JL. Stroke in patients with heart failure and reduced left ventricular ejection fraction. Neurology. 2000;54(2):288–294.
73. Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med. 1997;336(4):251–257.
74. Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. J Am Coll Cardiol. 1997;29(5):1074–1080.
75. Massie BM, Collins JF, Ammon SE, et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation. 2009;119(12):1616–1624.
76. Homma S, Thompson JL, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med. 2012;366(20):1859–1869.
77. Di Tullio MR, Sacco RL, Sciacca RR, Jin Z, Homma S. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol. 2007;49(7):797–802.
78. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events. Mayo Clin Proc. 2006;81(5):602–608.
79. Schneider B, Hanrath P, Vogel P, Meinertz T. Improved morphologic characterization of atrial septal aneurysm by transesophageal echocardiography: relation to cerebrovascular events. J Am Coll Cardiol. 1990;16(4):1000–1009.
80. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke. 1993;24(12):1865–1873.
81. Mattioli AV, Aquilina M, Oldani A, Longhini C, Mattioli G. Atrial septal aneurysm as a cardioembolic source in adult patients with stroke and normal carotid arteries. A multicentre study. Eur Heart J. 2001;22(3):261–268.
82. Berthet K, Lavergne T, Cohen A, et al. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke. 2000;31(2):398–403.
83. Pearson AC, Nagelhout D, Castello R, Gomez CR, Labovitz AJ. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol. 1991;18(5):1223–1229.
84. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001;345(24):1740–1746.
85. Pezzini A, Del Zotto E, Magoni M, et al. Inherited thrombophilic disorders in young adults with ischemic stroke and patent foramen ovale. Stroke. 2003;34(1):28–33.
86. Rajamani K, Chaturvedi S, Jin Z, et al. Patent foramen ovale, cardiac valve thickening, and antiphospholipid antibodies as risk factors for subsequent vascular events: the PICSS-APASS study. Stroke. 2009;40(7):2337–2342.
87. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology. 2000;55(8):1172–1179.
88. Homma S, DiTullio MR, Sacco RL, Sciacca RR, Mohr JP, Investigators P. Age as a determinant of adverse events in medically treated cryptogenic stroke patients with patent foramen ovale. Stroke. 2004;35(9):2145–2149.
89. Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study. J Am Coll Cardiol. 2006;47(2):440–445.
90. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP, Investigators PiCSSP. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation. 2002;105(22):2625–2631.
91. Kitsios GD, Dahabreh IJ, Abu Dabrh AM, Thaler DE, Kent DM. Patent foramen ovale closure and medical treatments for secondary stroke prevention: a systematic review of observational and randomized evidence. Stroke. 2012;43(2):422–431.
92. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012;366(11):991–999.
93. Rodan L, McCrindle BW, Manlhiot C, et al. Stroke recurrence in children with congenital heart disease. Ann Neurol. 2012;72(1):103–111.
94. Menache CC, du Plessis AJ, Wessel DL, Jonas RA, Newburger JW. Current incidence of acute neurologic complications after open-heart operations in children. Ann Thorac Surg. 2002;73(6):1752–1758.
95. Natowicz M, Kelley RI. Mendelian etiologies of stroke. Ann Neurol. 1987;22(2):175–192.
96. Scharf RE, Hennerici M, Bluschke V, Lueck J, Kladetzky RG. Cerebral ischemia in young patients: it is associated with mitral valve prolapse and abnormal platelet activity in vivo? Stroke.1982;13(4):454–458.
97. Rice GP, Ebers GC, Bondar RL, Boughner DR. Mitral valve prolapse: a cause of stroke in children? Dev Med Child Neurol. 1981;23(3):352–356.
98. Kouvaras G, Bacoulas G. Association of mitral valve leaflet prolapse with cerebral ischaemic events in the young and early middle-aged patient. Q J Med. 1985;56(219):387–392.
99. Barnett HJ, Boughner DR, Taylor DW, Cooper PE, Kostuk WJ, Nichol PM. Further evidence relating mitral-valve prolapse to cerebral ischemic events. N Engl J Med. 1980;302(3):139–144.
100. Burke A, Jeudy J, Virmani R. Cardiac tumours: an update: Cardiac tumours. Heart. 2008;94(1):117–123.
101. Kandt RS, Gebarski SS, Goetting MG. Tuberous sclerosis with cardiogenic cerebral embolism: magnetic resonance imaging. Neurology. 1985;35(8):1223–1225.
102. Furlan AJ, Craciun AR, Raju NR, Hart N. Cerebrovascular complications associated with idiopathic hypertrophic subaortic stenosis. Stroke. 1984;15(2):282–284.