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Print version ISSN 0102-7638
Rev Bras Cir Cardiovasc vol.26 no.3 São José do Rio Preto July/Sept. 2011
Graciane RadaelliI; Luiz Carlos BodaneseII; João Carlos Vieira da Costa GuaragnaIII; Anibal Pires BorgesIV; Marco Antonio GoldaniV; João Batista PetraccoVI; Jacqueline da Costa Escobar PiccoliVII; Luciano Cabral AlbuquerqueVIII
IIPhD in Cardiology by the Institute of Cardiology of Rio Grande do Sul / Baylor College of Medicine, Houston / Texas, Professor of Postgraduate Medicine and Health Sciences at the Pontificia Universidade Catolica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
IIIDoctor of Medicine from the Pontificia Universidade Catolica do Rio Grande do Sul, 2009; Head of Postoperative Cardiac Surgery HSL-PUCRS, Porto Alegre, Brazil
VIMedical Resident of the Residency Program in Cardiology, Hospital São Lucas da PUCRS, Porto Alegre, Brazil
VSpecialist in Cardiovascular Surgery, Chief of Cardiovascular Surgery of the HSL-PUCRS, Porto Alegre, Brazil
VIMaster of Cardiovascular Surgery, Chief of Cardiac Surgery of the HSL-PUCRS, Porto Alegre, Brazil
VIIPhD in Cell and Molecular Biology PUCRS, Adjunct Professor, Universidade Federal do Pampa - Campus Uruguaiana, Uruguaiana, RS, Brazil
VIIIDoctor of Health Sciences, Federal University of Rio Grande do Sul, 2006, Cardiovascular Surgeon at HSL-PUCRS, Porto Alegre, Brazil
BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce the chance of death, myocardial infarction (MI) and cerebrovascular accident (CVA) in patients with coronary disease. However there is no consensus as to its indication in patients undergoing coronary artery bypass grafting (CABG).
OBJECTIVE: To assess the relationship between preoperative use of ACE inhibitors and clinical outcomes after CABG.
METHODS: Retrospective cohort study. We included data from 3,139 consecutive patients undergoing isolated CABG in Brazilian tertiary care hospital between January 1996 and December 2009. Follow-up was until discharge or death. Clinical outcomes after surgery were analyzed between users and nonusers of ACE inhibitors preoperatively.
RESULTS: Fifty-two percent (n=1,635) of patients received ACE inhibitors preoperatively. The use of ACE inhibitors was an independent predictor of need for inotropic support (OR 1.24, 95% CI 1.01 to 1.47, P = 0.01), acute renal failure (OR 1.23, 95% CI 1.01 to 1.73, P = 0.04) and progression to atrial fibrillation (OR 1.32, 95% CI 1.02 to 1.7, P = 0.03) postoperatively. The mortality rate among patients receiving or not preoperative ACE inhibitors was similar (10.3% vs. 9.4%, P = 0.436), as well as the incidence of myocardial infarction and stroke (15.6% vs. 15.0%, P = 0.694 and 3.4% vs. 3.5%, P = 0.963, respectively).
CONCLUSION: The use of preoperative ACE inhibitors was associated with increased need for inotropic support and higher incidence of acute renal failure and postoperative atrial fibrillation, not associated with increased rates of myocardial infarction, stroke or death.
Descriptors: Angiotensin-converting enzyme inhibitors. Myocardial revascularization. Coronary disease. Coronary artery bypass.
Inhibitors of angiotensin-converting enzyme (ACE) inhibitors have been shown to be beneficial in preventing death, myocardial infarction (AMI) and stroke (CVA) in patients with coronary artery disease (CAD). They additional effects of ACE inhibitors are the control of high blood pressure (HBP) and the reduction of morbidity and mortality in heart failure also, being a mainstay in the treatment of this disease [1-3]. In addition, they play an important role in minimizing the occurrence of ischemic events after coronary artery bypass grafting (CABG) .
The ACE inhibitors should be given early to all patients with ventricular dysfunction or myocardial infarction, for the advantages of these drugs in relation to cardiac remodeling and the hemodynamics improvement (vasodilatation and afterload reduction). The decrease in mortality was observed either in clinical studies that selected patients with AMI and concomitant ventricular dysfunction (studies SAVE, AIRE and TRACE) as in studies that did not select a specific group, using ACE inhibitors in all patients with AMI for up to 1-4 years after the event (studies ISIS 4 and GISSI 3). Prolonged use of ACE inhibitors also resulted in cardiovascular benefits (HOPE study) . In addition to lowering blood pressure, ACE inhibitors act as anti-ischemic, through their protective effects of the vascular bed (antiatherosclerotic, antithrombotic and anti-inflammatory) [6,7].
There is growing evidence that ACE inhibitors should be used in all patients undergoing CABG. The Heart Outcomes Prevention Evaluation (HOPE)  demonstrated that therapy with ACE inhibitors benefits all patients with risk factors for cardiovascular disease as well as patients undergoing CABG. In the perioperative period, ACE inhibitors reduce inflammation and preserve endothelial function, improving long-term graft patency and minimizing the progression of existing atherosclerotic plaques.
There are still controversies over the preoperative use of ACE inhibitors in patients undergoing CABG. Studies suggest that the preoperative administration of ACE inhibitors in cases of CABG helps reduce systemic vascular resistance and the development of vasoplegia in the early postoperative phase, resulting in hypotension and renal dysfunction [8,9]. Other authors [10,11] suggest that preoperative use of ACE inhibitors does not cause hypotension and can be safely used in patients undergoing cardiac surgery.
The aim of this study was therefore to assess the relationship between the preoperative use of ACE inhibitors and clinical events after the completion of CABG.
We evaluated data from consecutive patients undergoing CABG at the Hospital São Lucas, Pontificia Universidade Catolica do Rio Grande do Sul (HSL-PUCRS) in Porto Alegre, Rio Grande do Sul, Brazil, between January 1996 and December 2009. We excluded those who had no information about the use or not preoperative ACE inhibitors or ARA2, and those undergoing concomitant valve replacement. In total, 3,139 patients met the inclusion criteria. Follow-up was during the period of hospitalization, or until hospital discharge or death.
After surgery, patients were admitted to the unit of Postoperative Cardiac Surgery (POCC) of the hospital. The information was taken from structured protocol completed by doctors or nurses of the unit in the pre-operative, perioperative and postoperative. The ejection fraction was measured by echocardiogram or radiocardiogram during hospitalization, and this data is available for more than 95% of patients. Patients were included in the ACE inhibitor group should be taking the drug or an angiotensin receptor antagonist 2 (ARA2) for at least 2 weeks.
The primary outcome assessed was the use of inotropic support after surgery, defined by need for vasopressor administration in the immediate postoperative period (24 to 48 hours). Secondary outcomes assessed were: acute renal failure (ARF), atrial fibrillation (AF), myocardial infarction, stroke and death. The preoperative use of ACE inhibitors or ARA2 was defined as the administration of medication in the same period to 24 hours before CABG. All outcomes, except for death were evaluated in the immediate postoperative period.
The diagnosis of ARF in the postoperative period was defined by an increase greater than or equal to 50% or serum creatinine greater than 0.5 mg/dL above the preoperative value. Postoperative AF was defined as the presence of AF of any duration observed in 12-lead electrocardiogram. The diagnosis of postoperative AMI was based on the current presence of subepicardial injury and the onset of Q wave, current of subendocardial injury with increased necrosis markers (troponin I or CK-MB), bundle branch block with new markers also high. Aiming to exclude the elevation of markers secondary to the procedure, it was only considered the increase of CK-MB of at least 5 times the reference value or greater than 10% of total CK or troponin I> 10 µg / dL after 12 hours of postoperative values as established by Nascente et al.  in the same population.
On the other hand, the diagnosis of stroke was defined as new neurological deficit consistent with findings on imaging (CT or MRI of the brain). The data were analyzed according to surgical priority: emergency (CABG should be done within a few hours), urgency (CABG should be performed during the same hospital) or elective (the patient's clinical status allowed readmission to hospital later to perform CABG).
As for the design, this was a retrospective cohort study.
The present study was assessed by the Research Ethics Committee of the Pontificia Universidade Catolica do Rio Grande do Sul (Registration 09/04811). Personal information obtained was kept confidential data being used exclusively for research. Because it is an observational study which evaluated only clinical and laboratory data of patients with no postoperative intervention or implication about the care provided, it was not applied the Informed Consent Form.
Continuous variables are described as mean ± standard deviation and categorical variables are described in percentages. The association between preoperative use of ACE inhibitors and clinical outcomes after surgery was evaluated by Student t test or chi-square as appropriate. Multivariate logistic regression analysis was performed to identify independent determinants of outcomes, and included those with P <0.2. The results are presented in percentages and odds ratio (OR) with confidence interval 95% (CI). The level of significance alpha was 0.05.
All statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) for Windows, version 12.0.
We evaluated 3,139 patients, being that in 1,635 (52.1%) we used ACE inhibitors or ARA2 in the pre-operatively (ACE inhibitors group) and in 1,504 (47.9%) we did not. Baseline characteristics of patients investigated are shown in Table 1. Apparently the ACE inhibitors group patients were more serious, because they had more comorbidities that were related to increased surgical risk as risk score of CABG recently published by our group . The patients in the ACE inhibitor group had a higher number of females, higher prevalence of advanced heart failure (functional classes III and IV of the New York Heart Association) and systolic dysfunction. There was a tendency to increased number of individuals with chronic AF. There was no difference between groups regarding age and the prevalence of renal disease (ESRD) and chronic obstructive pulmonary disease (COPD). There was less need for emergency surgery / emergency in the ACE inhibitor group.
The incidence of events evaluated in the post-CABG in patients who used and did not use ACE inhibitors in the preoperative period are shown in Figure 1. There was no difference in mortality between the groups (10.3% of deaths in the group who used ACE inhibitors vs. 9.4% in the group who did not use ACE inhibitors, P = 0.436).
The use of ACE inhibitors was the most used independent predictor of inotropic support in the postoperative period (OR 1.24, 95% CI 1.04 to 1.47, P = 0.015). Advanced age, heart failure functional class III or IV New York Heart Association (NYHA), urgent or emergency surgery, need for intra-aortic balloon and previous history of chronic renal failure, atrial fibrillation, myocardial infarction or cardiac surgery were also predictors of the need inotropic support after the procedure (Table 2).
Patients on ACE inhibitors had a higher risk of developing postoperative ARF (OR 1.23, 95% CI 1.01 to 1.73, P = 0.042), as well as elderly patients, patients with chronic obstructive pulmonary disease (COPD), heart failure, or CRF basal functional class III or IV heart failure patients, and those who required urgent or emergency surgery (Table 3).
The use of ACE inhibitors, after adjusting for age, was a predictor for the development of postoperative AF (OR 1.32, 95% CI 1.02 to 1.7, P = 0.032). In addition to age, COPD patients preoperatively also had a higher risk of AF (Table 4).
The preoperative use of ACE inhibitors did not increase the risk of AMI, stroke or death in post-CABG.
Some studies have shown that blocking the renin-angiotensin system (RAS) with ACE inhibitors improves ventricular function, prolongs survival and decreases the size of the infarct in patients after AMI  or patients with heart failure . However, it is unclear the role of ACE inhibitors in patients undergoing CABG. Surgeons attributed the beneficial effects of ACE inhibitors to their antihypertensive and antiatherogenic properties. Lazar et al.  concluded that all patients undergoing CABG should receive ACE inhibitors preoperatively.
The results of this study suggest that preoperative use of ACE inhibitors as an independent predictor of the need for inotropic support postoperatively, consistent with previously published data [17-20].
Perioperative hypotension, for generating a reduction in renal perfusion pressure is a known risk factor for the development of ARF in surgical patients. However, the association between therapy with ACE inhibitors and renal failure after cardiac surgery remains controversial . The effect of ACE inhibitors on renal function after surgery may depend on the prior exposure time. Rady & Ryan  found no significant association between use of ACE inhibitors and renal failure in post-cardiac surgery in patients chronically treated with medication. In contrast, Arora et al.  in a large observational study, showed significant association between preoperative use of ACE inhibitors and acute renal failure in the postoperative period of cardiac surgery and abdominal aortic surgery . In addition, there are reports that treatment with ACE inhibitors may increase the adverse effects during the first 3 months after surgery did not improve clinical outcome up to 3 years of follow up . On the other hand, the study APRES  showed that the use of long-term ramipril reduced the composite endpoint of cardiac death, myocardial infarction and heart failure in clinical treatment with revascularization. Our study suggested that use of ACE inhibitors in the pre-CABG increases the risk of ARF. As the follow-up occurred during the hospital stay, not have time to test whether there was a potential benefit of treatment as clinically important events.
A study by White et al.  in patients undergoing cardiac surgery (CABG and valve) showed a statistically significant association between the use of ACE inhibitors before surgery and reduce postoperative AF. Although we only evaluated patients undergoing CABG, our results are contradictory to the study cited, since there was an increased chance of developing postoperative AF. The blockade of the RAS in patients undergoing CABG contributes to the reduction of systemic vascular resistance and the vasoplegia in the immediate postoperative period, resulting in hypotension, which often requires volume and / or vasoactive drugs [17-20]. It is known that both the hypotension and volume overload are factors that contribute to the development of AF postoperatively .
Our study showed that preoperative use of ACE inhibitors did not increase the risk of AMI, stroke or death in post-CABG. In contrast, Miceli et al.  demonstrated that preoperative therapy with ACE inhibitors has increased at twice the risk of death in patients undergoing coronary artery bypass grafting. However, it is believed that other studies [29,30] did not show similar results due to small sample size to detect differences in mortality.
Interrupting the use of ACE inhibitors, or reducing the dose in the immediate postoperative period, and their reintroduction into the postoperative period, may be reasonable alternatives to minimize the acute effects, without loss of their chronic cardioprotective effects. Therefore, our work raises the hypothesis to be tested in future studies.
Our study has some limitations. The fact that it prevents the best observational evaluation of the intervention, making a hypothesis-generating study, whose results need further investigation with controlled trials. Patients who were using ACE inhibitors in the preoperative period had a higher number of comorbidities. We have no information of the real reason for not prescribing ACE inhibitors in the preoperative period. The use or nonuse of ACE inhibitors before surgery was an option of the doctor who referred the patient to the implementation of CRM. Even with an indication if we consider the underlying disease that caused the procedure, nearly half of the sample was not in use. In these patients, the ACE inhibitor was not prescribed in the hospital for a short period before surgery. In addition, we did not perform a separate analysis of treatment with ACE inhibitors or ARA2. During the study period, all revascularization procedures were performed by the same group of cardiac surgeons, with no significant changes in surgical technique. However, there was this period changes in the pharmacological treatment of ischemic heart disease that could be related to the incidence of outcomes.
The preoperative use of ACE inhibitors was associated with increased need for inotropic support postoperatively, and the higher incidence of ARF and AF not associated with an increased rate of myocardial infarction, stroke and death.
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Correspondence address: Article received on May 12th, 2011 Work performed at the Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil.
Avenida Ipiranga, 6690 - sala 300 - Serviço de Cardiologia
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Article accepted on July 14th, 2011
Article received on May 12th, 2011
Work performed at the Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil.