In patients with extensive comorbidities scheduled for major vascular surgery, a simple screening biomarker associated with adverse cardiac events would be useful for identifying those patients who might benefit from additional cardiac diagnostic testing or therapeutic interventions. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is synthesized in the ventricular myocardium in response to ventricular wall stress, such as in heart failure and coronary artery disease.1,2 It has been suggested that measurement of NT-proBNP levels might improve preoperative cardiac risk stratification for surgical patients.3–5 Anemia is independently related to both increased NT-proBNP levels6–8 and adverse cardiac outcome after vascular surgery.9 It is unknown whether the association between anemia and increased NT-proBNP levels is attributable to subclinical ventricular dysfunction, coronary artery disease, or both. Nonetheless, anemia may be an important confounding variable that may affect the prognostic value of NT-proBNP levels for predicting cardiac risk for surgical patients. To further increase the diagnostic accuracy of NT-proBNP for preoperative screening, it is important to identify factors that influence NT-proBNP levels and their interaction with identifying risk for adverse events. The purpose of this study was to evaluate whether anemia influences the prognostic value of preoperative NT-proBNP levels for identifying patients undergoing vascular surgery at risk for adverse cardiac events.
The study population consisted of 666 consecutive patients undergoing elective noncardiac vascular surgery at the Erasmus Medical Center, Rotterdam, The Netherlands, during the period June 2004 to April 2008. These patients were identified in a prospectively maintained database of all patients undergoing vascular surgery at this institution. The Medical Ethics Committee of the hospital was informed about the study, and all procedures of this retrospective study met with the approval of the Medical Ethics Committee of the Erasmus Medical Center.
Before surgery, a detailed cardiac history was obtained including the use of cardiovascular medication and the presence of cardiac risk factors. The latter included age, angina pectoris, prior myocardial infarction, history of heart failure or current congestive heart failure, prior stroke or transient ischemic attack, diabetes mellitus (fasting glucose level ≥7.0 mmol/L or medication to control diabetes), renal dysfunction (defined as an estimated glomerular filtration rate <60 mL · min−1 · 1.73 m−2 using the Modification of Diet in Renal Disease formula10), hypertension (arterial blood pressure ≥140/90 mm Hg or medical therapy to control hypertension), and hypercholesterolemia (plasma cholesterol level ≥5.5 mmol/L or treatment with lipid-lowering drugs). Other data collected included history of chronic obstructive pulmonary disease (defined as a forced expiratory volume in 1 s <70% of age and gender predictive value), site of surgery (abdominal aortic, peripheral, or carotid), and type of procedure (endovascular or open). Peripheral venous blood samples were obtained for measurement of hemoglobin and NT-proBNP levels in all patients during the preoperative outpatient clinic visit or at hospital admission. The NT-proBNP concentration was determined using an electrochemoluminescence assay on an Elecsys 2010 (Hoffman-La Roche, Basel, Switzerland). The method is a “sandwich”-type quantitative immunoassay based on polyclonal antibodies against epitopes in the N-terminal part of proBNP. The lower detection limit was 5 pg/mL. Intraassay coefficients of variance at 271 and 6436 pg/mL were 1.9% and 0.9%, respectively. Assays were performed by a laboratory technician blinded to the patients’ clinical data.
The preoperative hemoglobin value was defined as the last measurement obtained before surgery. Preoperative anemia was defined based on World Health Organization criteria as a serum hemoglobin level <13 g/dL for men and <12 g/dL for women.11
Preoperatively, patients underwent a 2-dimensional transthoracic echocardiographic examination at rest. Left ventricular (LV) ejection fraction (LVEF) was assessed in the apical, 4- or 2-chamber views. Quantification of the LV volumes was performed using the modified Simpson’s rule. The LVEF was calculated as (LV end systolic volume − LV end-diastolic volume) × 100/LV end-diastolic volume. Impaired LV systolic function was considered when the LVEF was <40%. Congestive heart failure was defined as suggestive clinical signs and symptoms with pulmonary congestion on chest radiograph in the presence of impaired LV function.
Twelve-lead electrocardiography (ECG) and serum cardiac troponin T measurements were performed immediately before surgery and on postoperative days 1, 3, 7, and 30 or at hospital discharge and whenever clinically indicated. ECG data were initially processed by a technician and analyzed by 2 experienced investigators who were blinded to patients’ clinical data. Troponin T level was measured using a whole blood rapid test (TropT version 2, Roche Diagnostics, Mannheim, Germany). The upper limit of normal for this assay is 0.03 ng/mL.
Study End Points
The primary end point of this study was the composite outcome of death within 30 days of surgery because of cardiac events, nonfatal myocardial infarction, and increased serum cardiac troponin T levels, which was considered to be a non–Q wave myocardial infarction. Cardiovascular death was defined as any death with a cardiovascular cause, including those deaths after a cardiac procedure, cardiac arrest, myocardial infarction, pulmonary embolus, stroke, or sudden deaths not ascribed to other causes. A myocardial infarction was defined as the presence of 2 of the following 3 criteria: 1) characteristic ischemic symptoms lasting >20 min, 2) ECG changes including acute ST elevation, followed by appearance of Q waves or loss of R waves, new left bundle-branch block, new persistent T wave inversion for at least 24 h, or new ST segment depression that persisted >24 h, or 3) a positive value for troponin T, defined as >0.10 ng/mL.12
Continuous data with a normal distribution are expressed as means and were compared using Student’s t-test. Continuous data with a significant skewed distribution are expressed as medians and were compared using the Mann-Whitney U-statistic test. Data are presented as percentages unless otherwise indicated. The association between hemoglobin and NT-proBNP plasma levels and the composite cardiovascular outcome was assessed using multivariable linear regression analysis adjusted for age (per decade), angina pectoris, myocardial infarction, heart failure, stroke, diabetes mellitus, renal dysfunction, and site and type of surgery. Receiver operating characteristic curve analysis was used to assess the optimal cutoff value of NT-proBNP for the prediction of the composite end point. The optimal value of NT-proBNP for predicting the postoperative composite cardiac outcome was defined as the concentration with the largest sum of sensitivity plus specificity. Univariable and multivariable logistic regression analyses were used to evaluate the relationship among anemia, increased levels of NT-proBNP, and the study end point. Interaction between anemia and NT-proBNP was evaluated by forcing this interaction term in the multivariable regression model. Subgroup analyses for the prognostic value of increased levels of NT-proBNP were conducted when there was a statistically significant interaction term. We report crude and adjusted odds ratios (ORs) and their 95% confidence intervals (95% CIs). For all tests, a P value <0.05 (2 sided) was considered significant. All analyses were performed using SPSS version 15.0 statistical software (SPSS, Chicago, Illinois).
Of the 666 patients, 250 underwent abdominal aortic aneurysm repair, 218 underwent lower limb arterial reconstructions, and 198 underwent carotid artery surgery. Baseline characteristics of the patients are presented in Table 1. Endovascular procedures comprised 30% of the studied surgical procedures (40% abdominal aortic, 8% lower limb, and 43% carotid artery). Most of the patients were men (76.6%), and the mean age was 68.2 ± 10.5 yr. Anemia was present in 206 patients (31%). Univariate factors associated with anemia were diabetes mellitus (P = 0.001), a history of a myocardial infarction (P = 0.010), previous coronary intervention (P < 0.001), renal dysfunction (P < 0.001), and heart failure (P = 0.002). Notably, patients with a history of stroke were less likely to have anemia (P = 0.002). Except for diuretics (P = 0.018), no association was seen between medication use and the incidence of anemia. Importantly, median levels of NT-proBNP were significantly higher in anemic compared with nonanemic patients (624.8 and 141.4 pg/mL, respectively; P < 0.001). Hemoglobin levels were inversely related to NT-proBNP levels (β coefficient for log-NT-proBNP for each 0.1-point increase in hemoglobin level was −0.063; P < 0.001).
Ninety-one patients (14.3%) experienced the composite end point of cardiovascular death, nonfatal myocardial infarction, or non–Q wave myocardial infarction. Of these patients, 41 (6.2%) experienced ECG changes compatible with myocardial infarction. Thirteen patients (1.9%) had a cardiovascular death.
Anemia was more frequent in patients with the composite cardiovascular end point compared with those without postoperative cardiac events (51.6% and 27.8%, respectively; P < 0.001). Moreover, baseline NT-proBNP levels in the patients with a postoperative cardiac event were significantly higher than in those without an event (763.1.3 and 169.2 pg/mL, respectively; P < 0.001). Using receiver operating characteristic curve analysis, the optimal value of NT-proBNP for predicting an adverse cardiac event was 350 pg/mL. The sensitivity and specificity of predicting this event for patients with a serum NT-proBNP level ≥350 pg/mL were 71% and 72%, respectively (area under the curve: 0.78; 95% CI: 0.72–0.83) (Fig. 1). In separate adjusted multivariate logistic regression models, the presence of preoperative anemia and increased levels of NT-proBNP were both predictive of postoperative cardiac events with ORs of 1.53 (95% CI: 1.07–2.99) and 4.09 (95% CI: 2.19–7.64), respectively (Table 2). The sensitivity of anemia for detecting the postoperative outcome is 56.0% and specificity 91.4%. Importantly, because the interaction term between anemia and NT-proBNP was significant (P = 0.004) for the prediction of the study end point, we conducted a subgroup analysis for nonanemic and anemic patients. Figure 2 shows that, after adjustment for clinical cardiac risk factors, and site and type of surgery, an increased level of NT-proBNP has no predictive value of the composite outcome in anemic (OR 2.16; 95% CI: 0.90–5.21) compared with nonanemic patients (OR 5.59; 95% CI: 2.23–13.97).
In this study, an association was observed between increased preoperative NT-proBNP levels and the risk for postoperative cardiac events in patients undergoing vascular surgery. However, our results demonstrate that anemia is a confounding factor in this relationship. Although preoperative NT-proBNP levels were additive to clinical risk factors for identifying risk for postoperative cardiovascular events in patients without anemia, NT-proBNP had less predictive value in those with anemia.
Postoperative cardiac events in patients undergoing vascular surgery are more common in patients with preoperative myocardial ischemia, LV dysfunction, and valve abnormalities compared with patients without these conditions.13,14 Several studies have shown that serum NT-proBNP is an independent predictor of postoperative cardiac events.3–5 Because NT-proBNP is synthesized in the ventricular myocardium in response to ventricular wall stress,1,2 the most obvious explanation for this association is increased ventricular pressure in response to myocardial ischemia and/or systolic dysfunction in patients prone to adverse postoperative cardiac events. In addition, noncardiac factors, such as renal dysfunction, pulmonary hypertension, chronic obstructive pulmonary disease, and body mass index, might influence NT-proBNP levels.15,16 In these patients with extensive comorbidities, an inexpensive, simple, and objective screening test can identify patients at increased risk.
Previous studies have shown that the presence of preoperative anemia increases the risk of death or serious morbidity,17,18 especially in patients with a history of cardiovascular disease.19 Recently, Dunkelgrun et al.9 studied the contribution of anemia to the risk of perioperative and long-term cardiac outcome in 1211 patients undergoing elective noncardiac open vascular surgery. They found that the presence and severity of anemia are significant predictors of 30-day and 5-yr cardiac events, regardless of underlying heart failure or renal dysfunction. Our findings that also included patients undergoing endovascular procedures seem to confirm these findings.
Anemia is common in patients with chronic heart failure and chronic renal insufficiency and is related to adverse outcomes in these populations.20,21 The cause of anemia is largely uncertain and is likely to be multifactorial. Lower hemoglobin levels can be associated with hemodilution (pseudoanemia) in heart failure20 or can be caused and/or worsened by various mechanisms, such as malnutrition,22 iron or vitamin deficiencies,22 and bone marrow depression caused by increased levels of proinflammatory cytokines.23 However, anemia may also enhance subclinical cardiac risk factors, such as mild coronary artery disease and LV dysfunction, because cardiac oxygen extraction ratio may be limited.24,25 In addition, heart failure can cause renal dysfunction as a consequence of forward failure leading to a reduction of renal perfusion and subsequently anemia by a reduction of erythropoietin production.26,27
In our study population using World Health Organization criteria for anemia,11 more than 30% of patients were anemic before surgery. Because NT-proBNP is released in response to ventricular plasma overload,28 NT-proBNP levels are higher in anemic compared with nonanemic patients. The effect of anemia on the plasma concentration of NT-proBNP has been reported in patients with heart failure and established coronary artery disease.29,30 Nonetheless, hemoglobin seems to be inversely associated with NT-proBNP even after adjustment for these factors.31 In this study, we found that anemia in vascular surgery patients was an independent predictor of NT-proBNP when adjusted for known confounders. Using multivariate analyses, we adjusted for heart failure and renal dysfunction, both factors frequently associated with fluid retention. Thus, one explanation for our findings of an independent association between anemia with NT-proBNP levels is that anemia may result in tissue hypoxemia32 or subclinical fluid retention resulting in hemodilution.33,34 These results raise the possibility that anemia may be associated with increased ventricular pressure and myocardial strain even before evidence of clinical ventricular dysfunction can be detected. This might confound the screening value of NT-proBNP to predict postoperative cardiac events, as is shown in our results.
The clinical implications of our findings are that patients scheduled for major vascular surgery could potentially be screened for adverse cardiac outcome with a relatively simple and objective test, NT-proBNP. However, especially in those patients who might benefit most, i.e., those with heart failure and renal disease in whom American College of Cardiology/American Heart Association guidelines recommend additional noninvasive testing,35 the prognostic value is reduced in the presence of anemia, whereas in nonanemic patients, the prognostic value is excellent.
The potential limitations of these data merit consideration. First, the study population consisted of patients referred to a tertiary referral center and may not fully represent a general population scheduled for elective vascular surgery. Second, our analyses are based on single baseline determinations of NT-proBNP and hemoglobin levels. As such, we could not address the potential importance of hemoglobin change over time, especially in patients with heart failure and renal dysfunction. Furthermore, the effects of unmeasured confounding variables or complex interactions between covariates, such as perioperative in-stent thrombosis, on the observed association and end points cannot be excluded. Third, we did not have enough information on preoperative blood transfusion to justly incorporate this in our analysis. Previous studies have shown divergent views regarding pre- and postoperative blood transfusion in vascular surgery, cardiac surgery, and patients with acute coronary syndromes.36–39 Further research is needed to assess the effect of preoperative correction of anemia in vascular surgery patients for the reduction of postoperative cardiac events. Regardless of these limitations, our study suggests that anemia should be considered during the interpretation of preoperative NT-proBNP levels. Moreover, it confirms the previous reports regarding the influence of anemia on NT-proBNP levels.
1. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med 2005;352:666–75
2. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, Ogawa H, Okumura K, Mukoyama M, Nakao K. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994;90:195–203
3. Yeh HM, Lau HP, Lin JM, Sun WZ, Wang MJ, Lai LP. Preoperative plasma N-terminal pro-brain natriuretic peptide as a marker of cardiac risk in patients undergoing elective non-cardiac surgery. Br J Surg 2005;92:1041–5
4. Dernellis J, Panaretou M. Assessment of cardiac risk before non-cardiac surgery: brain natriuretic peptide in 1590 patients. Heart 2006;92:1645–50
5. Feringa HH, Bax JJ, Elhendy A, de Jonge R, Lindemans J, Schouten O, van den Meiracker AH, Boersma E, Schinkel AF, Kertai MD, van Sambeek MR, Poldermans D. Association of plasma N-terminal pro-B-type natriuretic peptide with postoperative cardiac events in patients undergoing surgery for abdominal aortic aneurysm or leg bypass. Am J Cardiol 2006;98:111–5
6. Wold Knudsen C, Vik-Mo H, Omland T. Blood haemoglobin is an independent predictor of B-type natriuretic peptide (BNP). Clin Sci (Lond) 2005;109:69–74
7. Wu AH, Omland T, Wold Knudsen C, McCord J, Nowak RM, Hollander JE, Duc P, Storrow AB, Abraham WT, Clopton P, Maisel AS, McCullough PA. Relationship of B-type natriuretic peptide and anemia in patients with and without heart failure: a substudy from the Breathing Not Properly (BNP) Multinational Study. Am J Hematol 2005;80:174–80
8. Ralli S, Horwich TB, Fonarow GC. Relationship between anemia, cardiac troponin I, and B-type natriuretic peptide levels and mortality in patients with advanced heart failure. Am Heart J 2005;150:1220–7
9. Dunkelgrun M, Hoeks SE, Welten GM, Vidakovic R, Winkel TA, Schouten O, van Domburg RT, Bax JJ, Kuijper R, Chonchol M, Verhagen HJ, Poldermans D. Anemia as an independent predictor of perioperative and long-term cardiovascular outcome in patients scheduled for elective vascular surgery. Am J Cardiol 2008;101:1196–200
10. Froissart M, Rossert J, Jacquot C, Paillard M, Houillier P. Predictive performance of the modification of diet in renal disease and Cockcroft-Gault equations for estimating renal function. J Am Soc Nephrol 2005;16:763–73
11. Nutritional anaemias. Report of a WHO scientific group. World Health Organ Tech Rep Ser 1968;405:5–37
12. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol 2007;50:2173–95
13. Boersma E, Poldermans D, Bax JJ, Steyerberg EW, Thomson IR, Banga JD, van De Ven LL, van Urk H, Roelandt JR. Predictors of cardiac events after major vascular surgery: role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy. JAMA 2001;285:1865–73
14. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, Sugarbaker DJ, Donaldson MC, Poss R, Ho KK, Ludwig LE, Pedan A, Goldman L. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100:1043–9
15. DeFilippi C, van Kimmenade RR, Pinto YM. Amino-terminal pro-B-type natriuretic peptide testing in renal disease. Am J Cardiol 2008;101:82–8
16. de Lemos JA, Hildebrandt P. Amino-terminal pro-B-type natriuretic peptides: testing in general populations. Am J Cardiol 2008;101:16–20
17. Wu WC, Schifftner TL, Henderson WG, Eaton CB, Poses RM, Uttley G, Sharma SC, Vezeridis M, Khuri SF, Friedmann PD. Preoperative hematocrit levels and postoperative outcomes in older patients undergoing noncardiac surgery. JAMA 2007;297:2481–8
18. Beattie WS, Karkouti K, Wijeysundera DN, Tait G. Risk associated with preoperative anemia in noncardiac surgery: a single-center cohort study. Anesthesiology 2009;110:574–81
19. Carson JL, Duff A, Poses RM, Berlin JA, Spence RK, Trout R, Noveck H, Strom BL. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996;348:1055–60
20. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol 2002;39:1780–6
21. Al-Ahmad A, Rand WM, Manjunath G, Konstam MA, Salem DN, Levey AS, Sarnak MJ. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 2001;38:955–62
22. Anker SD, Negassa A, Coats AJ, Afzal R, Poole-Wilson PA, Cohn JN, Yusuf S. Prognostic importance of weight loss in chronic heart failure and the effect of treatment with angiotensin-converting-enzyme inhibitors: an observational study. Lancet 2003;361:1077–83
23. Weiss G. Pathogenesis and treatment of anaemia of chronic disease. Blood Rev 2002;16:87–96
24. Levy PS, Chavez RP, Crystal GJ, Kim SJ, Eckel PK, Sehgal LR, Sehgal HL, Salem MR, Gould SA. Oxygen extraction ratio: a valid indicator of transfusion need in limited coronary vascular reserve? J Trauma 1992;32:769–73; discussion 773–4
25. Levy PS, Kim SJ, Eckel PK, Chavez R, Ismail EF, Gould SA, Ramez Salem M, Crystal GJ. Limit to cardiac compensation during acute isovolemic hemodilution: influence of coronary stenosis. Am J Physiol 1993;265:H340–9
26. Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson PA, Harris PC. Edema of cardiac origin. Studies of body water and sodium, renal function, hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation 1989;80:299–305
27. Westenbrink BD, Visser FW, Voors AA, Smilde TD, Lipsic E, Navis G, Hillege HL, van Gilst WH, van Veldhuisen DJ. Anaemia in chronic heart failure is not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention as well. Eur Heart J 2007;28:166–71
28. Nakagawa O, Ogawa Y, Itoh H, Suga S, Komatsu Y, Kishimoto I, Nishino K, Yoshimasa T, Nakao K. Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. Evidence for brain natriuretic peptide as an “emergency” cardiac hormone against ventricular overload. J Clin Invest 1995;96:1280–7
29. Brucks S, Little WC, Chao T, Rideman RL, Upadhya B, Wesley-Farrington D, Sane DC. Relation of anemia to diastolic heart failure and the effect on outcome. Am J Cardiol 2004;93:1055–7
30. Mockel M, Muller R, Vollert JO, Muller C, Carl A, Peetz D, Post F, Kohse JK, Lackner KJ. Role of N-terminal pro-B-type natriuretic peptide in risk stratification in patients presenting in the emergency room. Clin Chem 2005;51:1624–31
31. Desai AS, Bibbins-Domingo K, Shlipak MG, Wu AH, Ali S, Whooley MA. Association between anaemia and N-terminal pro-B-type natriuretic peptide (NT-proBNP): findings from the Heart and Soul Study. Eur J Heart Fail 2007;9:886–91
32. Goetze JP, Gore A, Moller CH, Steinbruchel DA, Rehfeld JF, Nielsen LB. Acute myocardial hypoxia increases BNP gene expression. FASEB J 2004;18:1928–30
33. Androne AS, Katz SD, Lund L, LaManca J, Hudaihed A, Hryniewicz K, Mancini DM. Hemodilution is common in patients with advanced heart failure. Circulation 2003;107:226–9
34. Westenbrink BD, de Boer RA, Voors AA, van Gilst WH, van Veldhuisen DJ. Anemia in chronic heart failure: etiology and treatment options. Curr Opin Cardiol 2008;23:141–7
35. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof EL, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Buller CE, Creager MA, Ettinger SM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B, Tarkington LG, Yancy CW. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Developed in Collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol 2007;50:1707–32
36. Bursi F, Barbieri A, Politi L, Di Girolamo A, Malagoli A, Grimaldi T, Rumolo A, Busani S, Girardis M, Jaffe AS, Modena MG. Perioperative red blood cell transfusion and outcome in stable patients after elective major vascular surgery. Eur J Vasc Endovasc Surg 2009;37:311–8
37. Aronson D, Dann EJ, Bonstein L, Blich M, Kapeliovich M, Beyar R, Markiewicz W, Hammerman H. Impact of red blood cell transfusion on clinical outcomes in patients with acute myocardial infarction. Am J Cardiol 2008;102:115–9
38. Reeves BC, Murphy GJ. Increased mortality, morbidity, and cost associated with red blood cell transfusion after cardiac surgery. Curr Opin Anaesthesiol 2008;21:669–73
39. Karkouti K, Wijeysundera DN, Beattie WS. Risk associated with preoperative anemia in cardiac surgery: a multicenter cohort study. Circulation 2008;117:478–84