Anemia in intensive cardiac care unit patients - An underestimated problem

Advances in Medical Sciences

Volumn 60, Issue 2, 2015, Pages 307-314

  Uscinska, Ewa ^a   Idzkowska, Ewelina ^a   Sobkowicz, Bozena ^a   Musial, Wlodzimierz J ^a   Tycinska, Agnieszka M ^a  

^a MEDICAL UNIVERSITY OF BIALYSTOK   (Poland)

Author keywords

Anemia; Etiology; Intensive Cardiac Care Unit (ICCU); Treatment

Indexed keywords

HEMOGLOBIN; IRON;

ACUTE CORONARY SYNDROME; ACUTE HEART FAILURE; ANEMIA; BLEEDING; BLOOD TRANSFUSION; CARDIAC PATIENT; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR STENT; CHRONIC INFLAMMATION; CORONARY ARTERY BYPASS SURGERY; CRITICALLY ILL PATIENT; HEART ARRHYTHMIA; HEART INFARCTION; HEART LEFT VENTRICLE EJECTION FRACTION; HEART SURGERY; HEMATOCRIT; HEMOCONCENTRATION; HEMODILUTION; HUMAN; INCIDENCE; INTENSIVE CARDIAC CARE UNIT; INTENSIVE CARE UNIT; INVASIVE PROCEDURE; IRON BLOOD LEVEL; IRON DEFICIENCY; IRON METABOLISM; LENGTH OF STAY; MYOCARDIAL INFARCTION TYPE 1; MYOCARDIAL INFARCTION TYPE 2; NON ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; PATHOPHYSIOLOGY; PERCUTANEOUS CORONARY INTERVENTION; PHLEBOTOMY; PREVALENCE; PROGNOSIS; REVIEW; ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; SURGICAL MORTALITY; FEMALE; MALE; STATISTICS AND NUMERICAL DATA;

ANEMIA; FEMALE; HUMANS; INTENSIVE CARE UNITS; MALE;

EID: 84942315626     PISSN: 18961126     EISSN: 18984002     Source Type: Journal    
DOI: 10.1016/j.advms.2015.06.002     Document Type: Review

References (83)

1. B.J. Anía, V.J. Suman, V.F. Fairbanks, D.M. Rademacher, and L.J. Melton 3rd. Incidence of anemia in older people: an epidemiologic study in a well defined population J Am Geriatr Soc 45 7 1997 825 831
2. R.A. Archbold, D. Balami, A. Al-Hajiri, A. Suliman, R. Liew, J. Cooper, and et al. Hemoglobin concentration is an independent determinant of heart failure in acute coronary syndromes: cohort analysis of 2310 patients Am Heart 152 6 2006 1091 1095
3. E. Nikolsky, E.D. Aymong, A. Halkin, C.L. Grines, D.A. Cox, E. Garcia, and et al. Impact of anemia in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: analysis from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial J Am Coll Cardiol 44 3 2004 547 553
4. D. Aronson, M. Suleiman, Y. Agmon, A. Suleiman, M. Blich, M. Kapeliovich, and et al. Changes in haemoglobin levels during hospital course and long-term outcome after acute myocardial infarction Eur Heart J 28 11 2007 1289 1296
5. S.D. Anker, A. Voors, D. Okonko, A.L. Clark, M.K. James, S. von Haehling, et al. OPTIMAAL Investigators Prevalence, incidence, and prognostic value of anaemia in patients after an acute myocardial infarction: data from the OPTIMAAL trial Eur Heart J 30 11 2009 1331 1339
6. P.R. Lawler, K.B. Filion, T. Dourian, R. Atallah, M. Garfinkle, and M.J. Eisenberg Anemia and mortality in acute coronary syndromes: a systematic review and meta-analysis Am Heart J 165 2 2013 143-53.e5
7. A.C. Salisbury, K.J. Reid, A.P. Amin, J.A. Spertus, and M. Kosiborod Variation in the incidence of hospital-acquired anemia during hospitalization with acute myocardial infarction (data from 57 US hospitals) Am J Cardiol 113 7 2014 1130 1136
8. A.C. Salisbury, A.P. Amin, K.J. Reid, T.Y. Wang, F.A. Masoudi, P.S. Chan, and et al. Hospital-acquired anemia and in-hospital mortality in patients with acute myocardial infarction Am Heart J 162 2 2011 300-9.e3
9. N. Falluji, J. Lawrence-Nelson, J.B. Kostis, C.R. Lacy, R. Ranjan, and A.C. Wilson Effect of anemia on 1-year mortality in patients with acute myocardial infarction Am Heart J 144 4 2002 636 641 10.1016/S0002-8703(02)00134-5
10. A.C. Salisbury, M. Kosiborod, A.P. Amin, K.J. Reid, K.P. Alexander, J.A. Spertus, and et al. Recovery from hospital-acquired anemia after acute myocardial infarction and effect on outcomes Am J Cardiol 108 7 2011 949 954
11. A.C. Salisbury, K.J. Reid, K.P. Alexander, F.A. Masoudi, S.M. Lai, P.S. Chan, and et al. Diagnostic blood loss from phlebotomy and hospital-acquired anemia during acute myocardial infarction Arch Intern Med 171 18 2011 1646 1653
12. Y. Liu, Y.M. Yang, J. Zhu, H.Q. Tan, Y. Liang, and J.D. Li Anaemia and prognosis in acute coronary syndromes: a systematic review and meta-analysis J Int Med Res 40 1 2012 43 55
13. V. Kunadian, R. Mehran, A.M. Lincoff, F. Feit, S.V. Manoukian, M. Hamon, and et al. Effect of anemia on frequency of short- and long-term clinical events in acute coronary syndromes (from the Acute Catheterization and Urgent Intervention Triage Strategy Trial) Am J Cardiol 114 12 2014 1823 1829
14. M. Puurunen, T. Kiviniemi, W. Nammas, A. Schlitt, A. Rubboli, K. Nyman, and et al. Impact of anaemia on clinical outcome in patients with atrial fibrillation undergoing percutaneous coronary intervention: insights from the AFCAS registry BMJ Open 4 5 2014 e004700
15. A. Ariza-Solé, F. Formiga, J. Salazar-Mendiguchía, A. Garay, V. Lorente, J.C. Sánchez-Salado, and et al. Impact of anaemia on mortality and its causes in elderly patients with acute coronary syndromes Heart Lung Circ 2014 10.1016/j.hlc.2014.12.004 pii: S1443-9506(14)00818-X
16. D. Zindrou, K.M. Taylor, and J.P. Bagger Preoperative haemoglobin concentration and mortality rate after coronary artery bypass surgery Lancet 359 9319 2002 1747 1748
17. S. Bolińska, B. Sobkowicz, J. Zaniewska, I. Chlebińska, J. Boliński, R. Milewski, and et al. The significance of anaemia in patients with acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention Kardiol Pol 69 1 2011 33 39
18. J. Shiraishi, Y. Kohno, T. Nakamura, T. Yanagiuchi, S. Hashimoto, D. Ito, et al. AMI-Kyoto Multi-Center Risk Study Group Predictors of in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction in patients with a high Killip class Intern Med 53 9 2014 933 939
19. M.M. Vis, K.D. Sjauw, R.J. van der Schaaf, K.T. Koch, J. Baan Jr., J.G. Tijssen, and et al. Prognostic value of admission hemoglobin levels in ST-segment elevation myocardial infarction patients presenting with cardiogenic shock Am J Cardiol 99 9 2007 1201 1202
20. M.M. Vis, A.E. Engström, K.D. Sjauw, F.V. Tjong, J. Baan Jr., K.T. Koch, and et al. Plasma glucose and not hemoglobin or renal function predicts mortality in patients with STEMI complicated with cardiogenic shock J Cardiovasc Med (Hagerstown) 11 11 2010 827 831
21. C.H. Huang, C.C. Chang, C.L. Kuo, C.S. Huang, T.W. Chiu, C.S. Lin, and et al. Serum iron concentration, but not hemoglobin, correlates with TIMI risk score and 6-month left ventricular performance after primary angioplasty for acute myocardial infarction PLOS ONE 9 8 2014 e104495 10.1371/journal.pone.0104495
22. K. Thygesen, J.S. Alpert, H.D. White Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction Universal definition of myocardial infarction J Am Coll Cardiol 50 22 2007 2173 2195
23. M.P. Bonaca, S.D. Wiviott, E. Braunwald, S.A. Murphy, C.T. Ruff, E.M. Antman, and et al. ACC/AHA/ESC/WHF universal definition of myocardial infarction classification system and the risk of cardiovascular death: observations from the TRITON-TIMI 38 trial Circulation 125 4 2012 577 583
24. L. Saaby, T.S. Poulsen, S. Hosbond, T.B. Larsen, A.C. PyndtDiederichsen, J. Hallas, and et al. Classification of myocardial infarction: frequency and features of type 2 myocardial infarction Am J Med 126 9 2013 789 797
25. L. Saaby, T.S. Poulsen, A.C. Diederichsen, S. Hosbond, T.B. Larsen, H. Schmidt, and et al. Mortality rate in type 2 myocardial infarction: observations from an unselected hospital cohort Am J Med 127 4 2014 295 302
26. R.F. Riley, L.K. Newby, C.W. Don, K.P. Alexander, E.D. Peterson, S.A. Peng, and et al. Guidelines-based treatment of anaemic STEMI patients: practice patterns and effects on in-hospital mortality: a retrospective analysis from the NCDR Eur Heart J Acute Cardiovasc Care 2 1 2013 35 43
27. K.S. Rathod, D.A. Jones, V.S. Rathod, D. Bromage, O. Guttmann, S.M. Gallagher, and et al. Prognostic impact of anaemia on patients with ST-elevation myocardial infarction treated by primary PCI Coron Artery Dis 25 1 2014 52 59
28. S.M. Nazri, A. Constantine, R. Jagathesan, A. Kabir, J. Sayer, N. Robinson, and et al. The impact of haemoglobin reduction on short- and long-term mortality following primary percutaneous coronary intervention for ST-elevation myocardial infarction-analysis from a real world STEMI population Heart 100 Suppl. 3 2014 A17
29. A. Miceli, F. Romeo, M. Glauber, P.M. de Siena, M. Caputo, and G.D. Angelini Preoperative anemia increases mortality and postoperative morbidity after cardiac surgery J Cardiothorac Surg 9 2014 137 10.1186/1749-8090-9-137
30. A.H. van Straten, M.A. Hamad, A.J. van Zundert, E.J. Martens, J.P. Schönberger, and A.M. de Wolf Preoperative hemoglobin level as a predictor of survival after coronary artery bypass grafting: a comparison with the matched general population Circulation 120 2 2009 118 125
31. A. Boening, R.H. Boedeker, C. Scheibelhut, J. Rietzschel, P. Roth, and M. Schönburg Anemia before coronary artery bypass surgery as additional risk factor increases the perioperative risk Ann Thorac Surg 92 3 2011 805 810
32. M.L. Williams, X. He, J.S. Rankin, M.S. Slaughter, and J.S. Gammie Preoperative hematocrit is a powerful predictor of adverse outcomes in coronary artery bypass graft surgery: a report from the Society of Thoracic Surgeons Adult Cardiac Surgery Database Ann Thorac Surg 96 5 2013 1628 1634
33. S. Matsuda, T. Fukui, J. Shimizu, A. Takao, S. Takanashi, and H. Tomoike Associations between preoperative anemia and outcomes after off-pump coronary artery bypass grafting Ann Thorac Surg 95 3 2013 854 860
34. E.P. Stover, L.C. Siegel, R. Parks, J. Levin, S.C. Body, R. Maddi, and et al. Variability in transfusion practice for coronary artery bypass surgery persists despite national consensus guidelines: a 24-institution study Anesthesiology 88 2 1998 327 333
35. M.A. Rogers, N. Blumberg, S. Saint, K.M. Langa, and B.K. Nallamothu Hospital variation in transfusion and infection after cardiac surgery: a cohort study BMC Med 7 2009 37
36. S.A. Snyder-Ramos, P. Möhnle, Y.S. Weng, B.W. Böttiger, A. Kulier, J. Levin, et al. Investigators of the Multicenter Study of Perioperative Ischemia; MCSPI Research Group The ongoing variability in blood transfusion practices in cardiac surgery Transfusion (Paris) 48 7 2008 1284 1299
37. M. Engoren, T.A. Schwann, R.H. Habib, S.N. Neill, J.L. Vance, and D.S. Likosky The independent effects of anemia and transfusion on mortality after coronary artery bypass Ann Thorac Surg 97 2 2014 514 520
38. L.A. Hajjar, J.L. Vincent, F.R. Galas, R.E. Nakamura, C.M. Silva, M.H. Santos, and et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial JAMA 304 14 2010 1559 1567
39. S. Windecker, P. Kolh, F. Alfonso, J.-P. Collet, J. Cremer, V. Falk, and et al. 2014 ESC/EACTS guidelines on myocardial revascularization Eur Heart J 35 2014 2541 2619
40. G.M. Felker, K.F. Adams Jr., W.A. Gattis, and C.M. O'Connor Anemia as a risk factor and therapeutic target in heart failure J Am Coll Cardiol 44 5 2004 959 966
41. A. Cohen-Solal, C. Leclercq, G. Deray, S. Lasocki, J.J. Zambrowski, A. Mebazaa, and et al. Iron deficiency: an emerging therapeutic target in heart failure Heart 100 18 2014 1414 1420
42. F. Formiga, D. Chivite, O. Castañer, N. Manito, J.M. Ramón, and R. Pujol Anemia in new-onset congestive heart failure in patients admitted for acute decompensation Eur J Intern Med 17 3 2006 179 184
43. A. Palazzuoli, M. Gallotta, F. Iovine, R. Nuti, and D.S. Silverberg Anaemia in heart failure: a common interaction with renal insufficiency called the cardio-renal anaemia syndrome Int J Clin Pract 62 2 2008 281 286
44. D. Prakash Anemia in the ICU: anemia of chronic disease versus anemia of acute illness Crit Care Clin 28 2012 333 343
45. M. Sarraf, A. Masoumi, and R.W. Schrier Cardiorenal syndrome in acute decompensated heart failure Clin J Am Soc Nephrol 4 12 2009 2013 2026
46. S. von Haehling, J.C. Schefold, L.M. Hodoscek, W. Doehner, M. Mannaa, S.D. Anker, and et al. Anaemia is an independent predictor of death in patients hospitalized for acute heart failure Clin Res Cardiol 99 2 2010 107 113
47. J.B. Young, W.T. Abraham, N.M. Albert, W. GattisStough, M. Gheorghiade, B.H. Greenberg, et al. OPTIMIZE-HF Investigators and Coordinators Relation of low hemoglobin and anemia to morbidity and mortality in patients hospitalized with heart failure (insight from the OPTIMIZE-HF registry) Am J Cardiol 101 2 2008 223 230
48. A. Rovellini, G. Graziadei, C. Folli, A.M. Brambilla, R. Cosentini, C. Canetta, and et al. Causes and correlates of anemia in 200 patients with acute cardiogenic pulmonary edema Eur J Intern Med 23 8 2012 733 737
49. P. van der Meer, D. Postmus, P. Ponikowski, J.G. Cleland, C.M. O'Connor, G. Cotter, and et al. The predictive value of short-term changes in hemoglobin concentration in patients presenting with acute decompensated heart failure J Am Coll Cardiol 61 19 2013 1973 1981
50. A.S. Androne, S.D. Katz, L. Lund, J. LaManca, A. Hudaihed, K. Hrynkiewicz, and et al. Hemodilution is common in patients with advanced heart failure Circulation 107 2 2003 226 229
51. D.S. Silverberg, D. Wexler, M. Blum, G. Keren, D. Sheps, E. Leibovitch, and et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations J Am Coll Cardiol 35 7 2000 1737 1744
52. A.L. Baggish, R. van Kimmenade, A. Bayes-Genis, M. Davis, J.G. Lainchbury, C. Frampton, and et al. Hemoglobin and N-terminal pro-brain natriuretic peptide: independent and synergistic predictors of mortality in patients with acute heart failure. Results from the International Collaborative of NT-proBNP (ICON) Study Clin Chim Acta 381 2 2007 145 150
53. N. Hong, J.C. Youn, J. Oh, H.S. Lee, S. Park, D. Choi, and et al. Prognostic value of new-onset anemia as a marker of hemodilution in patients with acute decompensated heart failure and severe renal dysfunction J Cardiol 64 1 2014 43 48
54. L. Tarantini, F. Oliva, S. Cantoni, G. Cioffi, V. Agnoletto, G. Alunni, and et al. Prevalence and prognostic role of anaemia in patients with acute heart failure and preserved or depressed ventricular function Intern Emerg Med 8 2 2013 147 155
55. J.A. Ezekowitz, F.A. McAlister, and P.W. Armstrong Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure Circulation 107 2 2003 223 225
56. R. Miklík, M. Felsöci, J. Parenica, D. Tomcíková, J. Jarkovsky, and J. Spinar The prevalence of anemia and its impact on hospitalization mortality in patients with acute heart failure Vnitr Lek 56 5 2010 382 391
57. P.R. Kalra, T. Collier, M.R. Cowie, K.F. Fox, D.A. Wood, P.A. Poole-Wilson, and et al. Haemoglobin concentration and prognosis in new cases of heart failure Lancet 362 9379 2003 211 212
58. M.N. Zairis, N.G. Patsourakos, A.T. Georgilas, A. Melidonis, K.S. Argyrakis, A.A. Prekates, and et al. Anemia and early mortality in patients with decompensation of chronic heart failure Cardiology 119 3 2011 125 130
59. H.F. Groenveld, J.L. Januzzi, K.J. Damman, J. van Wijngaarden, H.L. Hillege, D.J. van Veldhuisen, and et al. Anemia and mortality in heart failure patients a systematic review and meta-analysis J Am Coll Cardiol 52 10 2008 818 827
60. L.H. Lund, E. Donal, E. Oger, C. Hage, H. Persson, I. Haugen-Löfman, and et al. Association between cardiovascular vs. non-cardiovascular co-morbidities and outcomes in heart failure with preserved ejection fraction Eur J Heart Fail 16 9 2014 992 1001
61. E.A. Jankowska, M. Kasztura, M. Sokolski, M. Bronisz, S. Nawrocka, W. Oles̈kowska-Florek, and et al. Iron deficiency defined as depleted iron stores accompanied by unmet cellular iron requirements identifies patients at the highest risk of death after an episode of acute heart failure Eur Heart J 35 36 2014 2468 2476
62. I. Rangel, A. Gonçalves, C. de Sousa, S. Leite, M. Campelo, E. Martins, and et al. Iron deficiency status irrespective of anemia: a predictor of unfavorable outcome in chronic heart failure patients Cardiology 128 4 2014 320 326
63. B.F. Makhoul, A. Khourieh, M. Kaplan, F. Bahouth, D. Aronson, and Z.S. Azzam Relation between changes in red cell distribution width and clinical outcomes in acute decompensated heart failure Int J Cardiol 167 4 2013 1412 1416
64. D.A. Pascual-Figal, J.C. Bonaque, B. Redondo, C. Caro, S. Manzano-Fernandez, J. Sánchez-Mas, and et al. Red blood cell distribution width predicts long-term outcome regardless of anaemia status in acute heart failure patients Eur J Heart Fail 11 9 2009 840 846
65. A. Cohen-Solal, T. Damy, M. Terbah, S. Kerebel, J.P. Baguet, O. Hanon, and et al. High prevalence of iron deficiency in patients with acute decompensated heart failure Eur J Heart Fail 16 9 2014 984 991
66. E. Uscinska, B. Sobkowicz, R. Sawicki, I. Kiluk, M. Baranicz, T. Stepek, and et al. Parameters influencing in-hospital mortality in patients hospitalized in intensive cardiac care unit: is there an influence of anemia and iron deficiency? Intern Emerg Med 10 3 2015 337 344
67. J.J. McMurray, S. Adamopoulos, S.D. Anker, A. Auricchio, M. Böhm, K. Dickstein, et al. ESC Committee for Practice Guidelines ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 Eur Heart J 33 14 2012 1787 1847
68. G. Filippatos, D. Farmakis, J.C. Colet, K. Dickstein, T.F. Lüscher, R. Willenheimer, and et al. Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial Eur J Heart Fail 15 11 2013 1267 1276
69. S.D. Anker, J. Comin Colet, G. Filippatos, R. Willenheimer, K. Dickstein, H. Drexler, et al. FAIR-HF Trial Investigators Ferric carboxymaltose in patients with heart failure and iron deficiency N Engl J Med 361 25 2009 2436 2448
70. F.J. Carrasco Sánchez, J.R. Iglesias, and J.G. Amorós Complementary treatment of acute heart failure in patients with diabetes, chronic obstructive pulmonary disease or anemia Med Clin (Barc) 142 Suppl. 1 2014 59 65
71. J.L. Vincent, Y. Sakr, and C. Lelubre The future of observational research and randomized controlled trials in red blood cell transfusion medicine Shock 41 Suppl. 1 2014 98 101
72. L. McIntyre, A.T. Tinmouth, and D.A. Fergusson Blood component transfusion in critically ill patients Curr Opin Crit Care 19 4 2013 326 333
73. P.C. Hébert, G. Wells, M.A. Blajchman, J. Marshall, C. Martin, G. Pagliarello, and et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care N Engl J Med 340 6 1999 409 417
74. J.L. Carson, M.L. Terrin, H. Noveck, D.W. Sanders, B.R. Chaitman, G.G. Rhoads, et al. FOCUS Investigators Liberal or restrictive transfusion in high-risk patients after hip surgery N Engl J Med 365 26 2011 2453 2462
75. C. Villanueva, A. Colomo, A. Bosch, M. Concepción, V. Hernandez-Gea, C. Aracil, and et al. Transfusion strategies for acute upper gastrointestinal bleeding N Engl J Med 368 1 2013 11 21
76. S. Chatterjee, J. Wetterslev, A. Sharma, E. Lichstein, and D. Mukherjee Association of blood transfusion with increased mortality in myocardial infarction: a meta-analysis and diversity-adjusted study sequential analysis JAMA Intern Med 173 2 2013 132 139
77. J.M. Silva Junior, E. Rezende, C.P. Amendola, R. Tomita, D. Torres, M.T. Ferrari, and et al. Red blood cell transfusions worsen the outcomes even in critically ill patients undergoing a restrictive transfusion strategy Sao Paulo Med J 130 2 2012 77 83
78. C.W. Hamm, J.P. Bassand, S. Agewall, J. Bax, E. Boersma, H. Bueno, et al. ESC Committee for Practice Guidelines ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation Eur Heart J 32 23 2011 2999 3054
79. M. Scharte, and M.P. Fink Red blood cell physiology in critical illness Crit Care Med 31 12 Suppl 2003 S651 S657
80. R.W. Taylor, L. Manganaro, J. O'Brien, S.J. Trottier, N. Parkar, and C. Veremakis Impact of allogenic packed red blood cell transfusion on nosocomial infection rates in the critically ill patient Crit Care Med 30 10 2002 2249 2254
81. I. Jelkmann, and W. Jelkmann Impact of erythropoietin on intensive care unit patients Transfus Med Hemother 40 5 2013 310 318
82. V. Mastromarino, M.B. Musumeci, E. Conti, G. Tocci, and M. Volpe Erythropoietin in cardiac disease: effective or harmful? J Cardiovasc Med (Hagerstown) 14 12 2013 870 878
83. Y. Wen, J. Xu, X. Ma, and Q. Gao High-dose erythropoietin in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized controlled trials Am J Cardiovasc Drugs 13 6 2013 435 442