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* From the Unità Operativa Cardiologia Riabilitativa (Drs. Ripamonti, Racca, and Ferratini), Centro di Bioingegneria (Dr. Castiglioni) and Laboratorio analisi (Dr. Calvo), IRCCS S. Maria Nascente Fondazione Don C.Gnocchi, Milan, Italy.
Correspondence to: Vittorio Racca, MD, Istituto S. Maria Nascente Fondazione Don Carlo Gnocchi, Via Capecelatro 66, 20148 Milano, Italy; e-mail: cardiologia{at}dongnocchi.it
Abstract
Objectives: Angiotensin-converting enzyme (ACE) inhibitors, which are frequently administered in patients with heart disease, have a known inhibitory effect on erythropoiesis. The aim of this study was to detect whether early ACE inhibitor administration slows recovery from anemia following recent cardiac surgery.
Methods and results: Forty male patients with anemia (hemoglobin < 12 g/dL) an average of 9 days after cardiac surgery were randomized to receive enalapril (ACE inhibitor group) or not. All of the patients received ferrous sulfate, 525 mg, in addition to standard therapy. Patients with anemia due to other causes were excluded. Blood samples were obtained at baseline, and after 8 days, 16 days, and 60 days. A 6-min walking test and echocardioscan were performed at baseline, and after 16 days and 60 days of treatment, and a chest radiograph was obtained at baseline and after 60 days. The ACE inhibitor group showed a statistically significant lower increase in hemoglobin and RBC values. The peak between-group differences of 1 g/dL of hemoglobin (p = 0.012) and 444 RBCs per milliliter (p = 0.017) were observed on day 16.
Conclusions: Early enalapril maleate administration in anemic patients after heart surgery significantly inhibits erythropoiesis. This unfavorable effect on anemia should be considered when prescribing ACE inhibitors for such patients.
Key Words: anemia • angiotensin-converting enzyme inhibitors • cardiac rehabilitation • heart surgery
Angiotensin-converting enzyme (ACE) inhibitors are frequently used after cardiac surgery for valvular diseases in patients with an overloaded volume,1 and a study2 has shown that they have positive effects on major cardiovascular end points in patients with ischemic heart disease and normal left ventricular function. Furthermore, their use has been recommended in the immediate preoperative period in order to reduce the risk of acute graft thrombosis,3 and they are often prescribed in patients after coronary artery bypass graft surgery. However, despite the increasing number of indications in cardiac patients,45678 published studies have shown that ACE inhibitors can inhibit erythropoiesis and reduce polyglobulia in renal transplant recipients,91011 worsen anemia in hemodialysis patients,12 and reduce hematocrit in patients with COPD13 or altitude polycythemia.14 The physiologic basis of this inhibitory effect is still unclear; some studies1516 have demonstrated the inhibition of erythropoietin synthesis, and others1718 have shown the induction of apoptosis in erythroid precursors affecting insulin-like growth factor-1, but there are probably also other ways in which ACE inhibitors inhibit erythropoietic activity.19
Postoperative anemia is frequent early after cardiac surgery, and the possible adverse inhibitory effects of ACE inhibitors on the RBC levels in such patients should be carefully evaluated. The aim of this study was to evaluate the effects of early administration of ACE inhibitors on erythropoiesis in patients with anemia after recent cardiac surgery.
Materials and Methods
This prospective, open-label study was approved by the Ethics Committee of our institute, and all of the patients gave their written informed consent. All of the male patients undergoing rehabilitation after on-pump cardiac surgery with sternotomy whose hemoglobin levels were 
12 g/dL and whose ejection fraction was > 40% (40 subjects) were enrolled and randomized to receive oral enalapril maleate (ACE inhibitor group) in addition to their standard therapy, or not (control group). Enrollment took place an average of 9 days after heart surgery.
All of the subjects had normal or slightly decreased left ventricular function and were administered the ACE inhibitor early with the aim of preventing possible cardiovascular events, and not for the legitimate hemodynamic and neurohormonal indication currently adopted in patients with left ventricular depression. Seventeen patients (42.5%), 9 in the control group and 8 in the treated group, received blood transfusions perioperatively: an average of 2.6 U and 3.0 U, respectively. None of the blood transfusions were administered later than the first day after surgery.
Both groups received a fixed dose of ferrous sulfate, 525 mg po, in addition to standard therapy. The patients with coronary artery disease were treated with ß-blockers and antiplatelet drugs, and those with valvular disease were treated with diuretics and anticoagulants. The exclusion criteria were as follows: (1) anemia secondary to preexisting diseases (blood or collagen diseases); (2) moderate or severe ventricular dysfunction (ejection fraction < 40%); (3) kidney failure with creatinine levels > 2 mg/dL; (4) GI bleeding; (5) infections and/or a body temperature > 38°C; and (6) COPD.
Follow-up
All of the patients underwent a baseline clinical evaluation and blood tests, including hemoglobin, RBC count, reticulocytes, serum iron, ferritin, transferrin, nitrogen, creatinine, and endogenous erythropoietin. Hemochromocytometry was performed (Se 9500; Dasit Spa; Cornaredo, Italy), as was blood chemistry (Synchron LX; Beckman-Coulter; Fullerton, CA), measurement of ferritin (Architect immunometry test; Abbott Laboratories; Abbott Park, IL), and evaluation of erythropoietin with an enzyme-linked immunosorbent assay reader (ELP-40; Bouty; Milan, Italy) and strip washer (Microplate; Bio-Tek Instruments; Winooski, VT).
Routine cardiology tests included ECG, chest radiography, color Doppler echocardiography, and 6-min walking test (6MWT). Left ventricular ejection fraction (LVEF) was measured echocardiographically by means of an apical four-chamber scan and the Simpson biplane method. All of the blood chemistry tests were repeated on days 8, 16, and 60; echocardiography and 6MWT on days 16 and 60; and chest radiography on day 60.
Statistical Analysis
The differences in hemoglobin and RBC values were statistically assessed by means of analysis of variance for repeated measures, with the between-group factor being the treatment, and the within-group factor being the time of follow-up. When one of the two factors or their interaction was significant, post hoc analysis was performed by Fisher least-significant difference test (Statistica 6.0; Statsoft; Tulsa, OK). The between-group differences in LVEF, cardiothoracic ratio, and 6MWT were tested using an unpaired t test. In order to investigate further the mechanisms influencing the recovery from anemia, we also performed a multiple regression analysis using the increase in hemoglobin observed 16 days after enrollment as the dependent variable, and presurgical clinical variables (age, body mass index, hemoglobin, and creatininemia) as independent variables. A significance level of p < 0.05 was considered statistically significant.
Results
The baseline demographic and clinical characteristics of the patients are shown in Table 1 . The two groups had the same age and were similar in terms of the number of postoperative days at the time of enrollment, clinical condition, and pharmacologic and transfusion treatments received in addition to standard therapy. On entry, all of the patients had a clinical picture consistent with anemia (hemoglobin, 10.65 ± 0.9 g/dL [± SEM]; RBC count, 3,572,000 ± 340,000/mL) without any significant difference between the two groups. None of the patients had blood loss during the observation period. Table 2 shows the main hematologic parameters. The data on day 1 were consistent with anemia in critically ill patients; subsequently, there was a progressive increase in iron levels and decrease in ferritin levels due to the recovery from surgical injury. The dose of enalapril maleate administered to the ACE inhibitor group was progressively increased to the maximum tolerated dose of 11.75 ± 7.3 mg at the third control examination.
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Anemia is frequent in patients who have undergone cardiovascular surgery. The complex pathogenesis of anemia may be due to a combination of many factors, such as perioperative bleeding, extracorporeal circulation (ECC), hemolysis, inhibition of bone marrow function for various reasons, nutritional deficiencies, and infections. Drugs that interfere with erythropoiesis may be detrimental in such patients, and a recent study20 has shown that chronic ACE inhibitor administration in patients with left ventricular dysfunction is associated with a 52% increase in the odds of new anemia after 1 year.
The aim of our study was to verify the effects on hemoglobin and RBC values of early postoperative ACE inhibitor administration in a well-defined population of male patients with normal or slightly reduced left ventricular function who underwent a major cardiovascular surgery with sternotomy and ECC. We only enrolled male patients in order to ensure a more homogeneous set of data, bearing in mind the different range of standard values between the two sexes. The patients randomized to receive the ACE inhibitor had lower absolute and progressive mean hemoglobin and RBC values than those in the control group. The greatest difference in hemoglobin concentration (1 g/dL; p = 0.012) was observed on the 16th day of treatment, after which it gradually decreased and had become nonsignificant by day 60; there was a similar large difference in RBC levels on the same day (444 per milliliter; p = 0.017).
It is worth noting that 13 patients treated with enalapril (vs 6 patients in the control group) showed no increase from baseline hemoglobin levels after 8 days, and hemoglobin values had actually decreased in 9 patients (vs 4 patients in the control group); furthermore, 8 patients in the ACE inhibitor group (vs only 2 patients in the control group) had persistently lower hemoglobin levels than at the time of study enrollment. This effect was observed even if the doses of enalapril were low, the maximal doses that could been achieved in these patients (average, 11.75 mg/d); these findings increase the significance of our results.
Although it could be expected that there would be more reticulocytes in the group not treated with ACE inhibitors, we did not find any difference between the two groups. We do not have a clear explanation for this but can speculate that the method used was not sensitive enough to reveal small differences in reticulocyte counts.
Sixty days after study enrollment, mean hemoglobin and RBC levels in both groups converged toward physiologic levels but remained persistently (but not significantly) lower in the ACE inhibitor group. In the postoperative period, when a prompt erythropoiesis response is crucial, the positive actions of these drugs may be counterbalanced by persistent anemia, thus leading to a slower functional recovery. This could be particularly true in patients with severe left ventricular depression or elderly patients (paradoxically, the very patients who would most benefit from the effects of ACE inhibitors21), whereas the successful treatment of anemia is associated with a significant improvement in cardiac function and a reduction in the duration of hospitalization.22
All of the patients in our study, however, had normal or slightly decreased left ventricular function because we wanted to investigate the appropriateness of early using ACE inhibitors and their effect on the recovery of anemia. A specific clinical trial is required to evaluate whether a clinical impact of anemia on rehabilitation outcome actually exists for patients with more severe ventricular dysfunction. As was expected in our patients, moderate inhibition of erythropoiesis did not lead to any significant functional changes. The 6MWT, LVEF, and cardiothoracic ratio showed no statistically significant differences between the two groups at follow-up, although a slightly more favorable trend in the patients who had not received ACE inhibitors was observed.
It can be suggested that patients may be particularly sensitive to factors inhibiting erythropoiesis after cardiovascular surgery. The results of this open-label, randomized study are based on objective quantitative laboratory data and cardiologic diagnostic examinations carried out by physicians who were unaware of the randomization, and so significant selection and/or placebo effect biases can be excluded. The study results must of course be considered as referring to enalapril maleate, although the inhibition of erythropoiesis seems to be a class effect of ACE inhibitors.
Conclusions
Our study shows that the early administration of enalapril maleate to patients with anemia who had recently undergone major cardiovascular surgery with thoracotomy and ECC led to a significant, transient inhibition of erythropoiesis. The indication of early treatment with this drug in this particular population should consider this possible unfavorable effect on blood components.
Footnotes
Abbreviations: ACE = angiotensin-converting enzyme; ECC = extracorporeal circulation; LVEF = left ventricular ejection fraction; 6MWT = 6-min walking test
This work was performed at Istituto S. Maria Nascente Fondazione Don Carlo Gnocchi, Milan, Italy.
The authors have no conflicts of interest related to this article.
Received for publication June 24, 2005. Accepted for publication December 23, 2005.
References
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