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The aim of the present study was to determine whether oral pretreatment with micronized purified flavonoid fraction (Daflon) has beneficial effects on cardiac function and outcome after cardiac operations.
This prospective, randomized trial enrolled 43 patients who had an impaired preoperative left ventricular ejection fraction of less than 0.50 (mean, 0.45 ± 0.04) and a mean New York Heart Association functional class status of 2.30 ± 0.74; all were scheduled for elective coronary artery bypass grafting. Patients who were randomized to the Daflon group (n=21) received oral Daflon 500 mg (6 tablets daily for 4 days, followed by 2 tablets for 3 days) preoperatively. Outcome variables included perioperative hemodynamic data, inotropic requirements, morbidity, and death, as well as cardiac ischemia and various outcome markers. Hemodynamic and biochemical data were collected before induction of anesthesia, perioperatively before starting cardiopulmonary bypass, immediately after bypass, and at the 24th postoperative hour.
There was only 1 death (in the Daflon group). During the post-cardiopulmonary bypass period, troponin I and lactate dehydrogenase levels were significantly lower in the Daflon group. Also, the New York Heart Association status of the patients in the Daflon group was significantly lower postoperatively. Differences between the 2 groups in lengths of stay in the intensive care unit and hospital, inotropic requirements, and left ventricular ejection fraction levels did not reach statistical significance.
Orally administered Daflon might provide better outcomes for patients who have impaired cardiac function before undergoing cardiac operations that require cardiopulmonary bypass.
Daflon® 500 mg (Les Laboratoires Servier, a Servier company; Neuilly-Sur-Seine, France) is a micronized purified flavonoid fraction (MPFF) containing 90% diosmin and 10% flavonoids expressed as hesperidin. Early restoration of blood flow to ischemic tissue is essential to stop the progression of cellular injury that is secondary to the decrease in oxygen and nutrient delivery. However, it is now clear that reperfusion to an ischemic area initiates a complex cascade of pathologic events that could lead to the same result as prolonged hypoxia (that is, cellular dysfunction and necrosis). Micronized purified flavonoid fraction has been shown to modify the interaction between leukocytes and endothelium.1 Micronized purified flavonoid fraction acts favorably on the complications of microcirculatory dysfunction by normalizing the synthesis of prostaglandins and free radicals. In a study in human beings, MPFF administration was found to result in minor side effects in only 10% of the subjects, compared with 13.9% of those treated with placebo.2
The aims of the present randomized clinical trial were to examine the efficacy of pretreatment with oral MPFF (Daflon) in patients with impaired left ventricular (LV) function scheduled for coronary artery bypass grafting (CABG) and to investigate whether Daflon could protect the heart against ischemia–reperfusion injury after CABG and could affect the postoperative outcomes. Admittedly, it can be difficult to distinguish systemic inflammation from the ischemia–reperfusion injury secondary to cardiac surgery performed with cardiopulmonary bypass (CPB): both affect cardiac performance and contribute to the transient depression of myocardial contractility that is commonly seen postoperatively.
From February 2006 through February 2007, 43 patients scheduled for CABG at the University Hospital of Ankara Heart Center were prospectively enrolled in the study. After approval by the local ethics committee, written informed consent was obtained from all patients who were scheduled for elective CABG and thought to meet the eligibility criteria. Inclusion criteria were as follows: greater than 70% stenosis of at least 2 coronary arteries; left ventricular ejection fraction (LVEF) lower than 0.50; and a medium-risk EuroSCORE (3–5).3 Patients were excluded if they had significant coexistent disease; greater than 70% carotid stenosis; recent (<3 wk) stroke; renal insufficiency (estimated creatinine clearance, >60 mL/min, according to the Cockcroft-Gault formula); chronic respiratory disease (arterial oxygen pressure, <7 kPa on room air); or liver insufficiency (aspartate transaminase or alanine transaminase, >2 times the upper range). Eligible patients were randomized to 1 of 2 groups: the Daflon (study) group and the placebo (control) group. Block randomization was used to keep the number of subjects in the 2 groups closely balanced. The attending physicians and nurses were blinded to which patient was in which group.
Patients who were randomized to the Daflon group (n=21) received, during the 7 days leading up to surgery, oral Daflon 500 mg (6 tablets daily for 4 days, followed by 2 tablets for 3 days).
All patients were given oral diazepam before anesthesia induction and 1.5 g cefuroxime as an antibiotic prophylaxis. Anesthesia was induced intravenously with 0.04 mg/kg midazolam, 5 to 10 mg/kg fentanyl, and 0.1 mg/kg pancuronium. Anesthesia was maintained with 0.8 mg/kg/min of midazolam and 0.08 mg/kg/min of fentanyl by continuous infusion. Pancuronium was given as needed to maintain neuromuscular blockade. All patients underwent cardiac surgery with the aid of nonpulsatile CPB by means of roller pumps and disposable membrane oxygenators. The pump was primed with 1,200 mL of lactated Ringer's solution, to which 100 mmol of sodium bicarbonate and 5,000 IU of heparin were added. After systemic heparin administration (1 mg/kg), cardiopulmonary bypass was instituted at a flow rate of 2.4 L/min/m2 body surface area. During CPB, the mean arterial pressure target was set at 60 mmHg, and the core temperature of the patients was allowed to drift to 30–32°C during CPB. Alpha-stat pH management (mild hypercapnia) was used. Intermittent cold-blood cardioplegic solution (1:4 blood-to-crystalloid solution, with maximal potassium concentration 22 mEq/L) was delivered antegrade via the aortic root. Cross-clamp, total CPB, and operative times were recorded, and all patients received at least 1 internal mammary artery graft on the left anterior descending coronary artery.
Venous blood samples were collected sequentially (at baseline before surgery, at operation before CPB, immediately after CPB, and at the 24th postoperative hour) for measurements of cardiac troponin I, creatine kinase, myocardial fraction of creatine kinase, lactate, myoglobulin, white blood cell count, aspartate transaminase, alanine transaminase, blood urea nitrogen, creatinine, fibrinogen, D-dimer, erythrocyte sedimentation rate, lactate dehydrogenase, uric acid, and C-reactive protein. Samples were analyzed at the Department of Clinical Biochemistry, Ankara University, with an immunoassay analyzer (Access® AccuTnI™, Beckman Coulter, Inc.; Brea, Calif).
Hemodynamic measurements (data not shown: mean arterial pressure, heart rate, and central venous pressure), and echocardiographic recordings (LVEF, and LV end-diastolic and end-systolic diameters) were obtained at baseline and again at the 24th hour after surgery.
Preoperative electrocardiographic results, inotropic medications, and intra-aortic balloon pump (IABP) requirements were recorded preoperatively and for the first 24 hours after surgery. The in-hospital mortality rate, hemodynamic changes, the need for pharmacologic cardiac or IABP support, and the incidence of cardiovascular complications (new Q-wave on electrocardiography, atrial fibrillation, and conduction blockade requiring electrical stimulation) were also recorded. All patients were monitored until hospital discharge to detect any adverse events.
Nominal variables were evaluated by the χ2 test or the Fisher Exact test, where applicable. The 2-way repeated-measures analysis of variance was used to test the differences in measurement between the times before and immediately after the induction of CPB and to compare the Daflon and control groups in terms of biomarkers. Logarithmic transformation was applied for some of the continuous variables that did not meet test assumptions. For statistical analyses, SPSS for Windows 11.0 (SPSS Inc.; Chicago, Ill) was used. A P value of less than 0.05 was considered significant.
Data were obtained in 43 patients (22 in the control group and 21 in the Daflon group). The study sample size was found to show a 30% reduction of the mean levels of postoperative troponin I levels in patients who were administered Daflon, with an α-error of 5% and a β-error of 20%, yielding a power of 80%.
Demographic, clinical, echocardiographic, and biochemical laboratory values were similar in the 2 groups preoperatively, as were surgical variables (Table I). Preoperatively, all patients had echocardiographic characteristics of impaired LV function (LVEF, <0.50); the overall mean EuroSCORE was 5 ± 1.5 (upper limit for medium risk), and the overall New York Heart Association (NYHA) status was 2.3 ± 0.74. Postoperatively, all hemodynamic and echocardiographic variables of the 2 groups were comparable (Table II).
Postoperatively, the mean NYHA status of each group decreased significantly (from 2.24 ± 0.7 to 1.33 ± 0.48 in the Daflon group, and from 2.36 ± 0.79 to 1.73 ± 0.55 in the control group; P <0.001). In spite of this decrease in both groups, the final NYHA status of the patients was significantly better in the Daflon group (P=0.02).
Of all the biomarkers studied, only the levels of lactate dehydrogenase and cardiac troponin I were significantly lower in the Daflon group immediately after CPB, when compared with the study group (P=0.038 and P=0.003, respectively). There were no statistically significant differences between the groups in the rest of the biomarkers studied (Table III).
Postoperative complications are shown in Table II. The number of patients with atrial fibrillation in the postoperative period was similar in both groups. None of the patients experienced a stroke or renal or respiratory failure. The need for inotropic support and an IABP in the postoperative period were similar between the groups. One patient in the Daflon group died on the 19th postoperative day of a myocardial infarction. Similar between groups were the duration of intubation (P=0.941) and of stays in the intensive care unit (P=0.798) and the hospital (P=0.424).
Cardiac surgery performed with the aid of CPB provokes a systemic inflammatory response that is triggered by the exposure of blood to the foreign surfaces of the extracorporeal circuit, as well as by the surgical trauma itself. The initiation of CPB is preceded by aortic cross-clamping and cardiac arrest, which renders the heart globally ischemic and entails myocardial ischemia–reperfusion injury. Myocardial ischemia–reperfusion injury promotes a local inflammatory response characterized by the release of cytokines and adhesion molecules, which in turn is responsible for the activation of the endothelium and the adhesion of leukocytes.4,5
In the absence of experimental models of venous disease, the activity of MPFF has been investigated in pharmacologic models that elicit alterations of the microcirculation like those observed in chronic venous insufficiency. Several studies have been performed in models of ischemia–reperfusion,6,7 inflammation evoked by edematogenic substances,8 oxidant challenge,6,9 venular occlusion,10 and transcapillary fluid shift after postural changes.11
The duration of treatment has ranged from 1 to 25 days, and most studies have been performed by means of intravital microscopy, which enables direct visualization of the microcirculation in various tissues. Pretreatment of hamster striated muscle with MPFF for 8 days before 4 hours of ischemia (by tourniquet) prevented damage to the muscle fiber, probably by reducing the number of extravasated leukocytes.8
Our results obtained with MPFF are in agreement with those of previous experiments performed under similar conditions.12,13 Oral treatment with MPFF, at 20 mg/kg per day for 10 consecutive days, significantly reduced the increase in macromolecular permeability induced by ischemia–reperfusion (103.6 ± 15.4 vs 42.6 ± 9.3 leaks/cm2; P <0.01).
The effects of MPFF on the increase in microvascular macromolecular permeability have been confirmed in different experimental models and species.6,7 Micronized purified flavonoid fraction also reduces leukocyte adhesion to endothelial cells of postcapillary venules in various experimental models (ischemia–reperfusion, venular occlusion/reperfusion, and oxidant challenge), as revealed by intravital microscopy or histomorphologic analysis.6,8,9,14 Leukocyte adhesion, which seems to play a major role in the pathogenesis of venous disease, is an important process for vascular integrity but is implicated in reperfusion injury.15 Flavonoids have been shown to have wide-spectrum beneficial effects in treating chronic venous disease16 and skin disorders17 and in promoting anastomosis.18
At first we used the high dose of Daflon suggested for severe hemorrhoidal attacks (6 tablets daily for 4 days), followed by the routine dose of 2 tablets for 3 days, to achieve sufficient plasma levels of the drug in our study. Examination for the BIAS study19 of the predictive value of inflammatory biomarkers in patients with acute coronary syndromes has shown that elevated circulating levels of C-reactive protein, cardiac troponin I, and fibrinogen can each confer incremental prognostic information—independent of other clinical risk predictors—for the incidence of cardiovascular death at 5 years.
The scope of our laboratory analysis was determined by mortality-related laboratory values; by other, recently described biomarkers associated with increased risk of in-hospital death among critically ill patients; and by specific markers of myocardial cell damage and predictors of outcome.20–22
A study by Yavuz and colleagues23 showed a cardioprotective effect (by alternative complement activation inhibition) of PMFF against reperfusion injury. In comparison with that study, we studied many more biomarkers, limited the operative procedures to CABG in patients with impaired LV function, and observed postoperative outcomes. The findings of significantly lower levels of cardiac troponin I and lactate dehydrogenase during the post-CPB period in the Daflon group, compared with the control group, suggest a possible protective effect against myocardial ischemia during CABG in patients who receive a high dose of MFPP.
Our study fails to show any differences in cytokines between the groups; therefore, we are not able to place emphasis on the effect of oral pretreatment with MFPP on attenuation of inflammatory response. Further research is required to establish whether the anti-inflammatory effects of this pretreatment can overcome the powerful inflammatory stimulus provoked by CPB. Nevertheless, these data support our assumption that pretreatment with oral MFPP might be beneficial in patients with impaired LV function who are undergoing CABG. It should be noted that our study included only moderately high-risk patients with impaired LVEF, medium EuroSCORE, and high NYHA status. It is obvious that further research is required to establish whether pretreatment with MFPP could serve as a novel pharmacologic strategy to improve cardiac protection during cardiac surgery that involves CPB. We infer that improvement in clinical outcomes for CABG patients pretreated with MFPP can be demonstrated in a larger study that enrolls patients who have LV function worse than that of our patients.
Address for reprints: Evren Ozcinar, MD, Heart Center, Department of Cardiovascular Surgery, Ankara University School of Medicine, Dikimevi–Ankara 06340, Turkey