High target hemoglobin with erythropoiesis-stimulating agents has advantages in the renal function of non-dialysis chronic kidney disease patients
Therapeutic Apheresis and Dialysis. 2012;16((6):):529-40.
We investigated the long-term effects of maintaining high hemoglobin (Hb) on renal function in patients with chronic kidney disease not on dialysis. Subjects (Hb < 10 g/dL and serum creatinine (Cr) 2-6 mg/dL) were randomized to either a high Hb group (N = 161, 11.0 <= Hb < 13.0 g/dL) receiving darbepoetin alfa or to a low Hb group (N = 160, 9.0 <= Hb < 11.0 g/dL) with epoetin alfa, stratified according to baseline Hb and serum Cr levels, comorbidity of diabetes, and study centers. Primary endpoints were composites of the following events: doubling of serum Cr, initiation of dialysis, renal transplantation, or death. Three-year cumulative renal survival rates (95% CI) were 39.9% (30.7-49.1%) and 32.4% (24.0-40.8%) in the high and low Hb groups, respectively (log-rank test; P = 0.111). A Cox proportional-hazards model adjusted by age, sex and the randomization factors showed a significantly lower event rate in the high Hb group (P = 0.035). The estimated hazard ratio (95% CI) for the high versus the low Hb group was 0.71 (0.52-0.98), the risk reduction was 29% in the high Hb group. Incidences of serious adverse cardiovascular events did not differ significantly between the high and low Hb groups (3.1% and 4.4%, respectively). No safety issues were noted in either group. Maintaining higher Hb levels with darbepoetin alfa better preserved renal function in patients with chronic kidney disease not on dialysis. 2012 The Authors. Therapeutic Apheresis and Dialysis 2012 International Society for Apheresis.
Positive outcomes of high hemoglobin target in patients with chronic kidney disease not on dialysis: a randomized controlled study
Therapeutic Apheresis and Dialysis. 2011;15((5):):431-40.
Correcting anemia in patients with chronic kidney disease (CKD) to higher hemoglobin (Hb) levels may be associated with increased risk. No optimal target for Hb has been established. This controlled study examined 321 patients with CKD who were not on dialysis, had a Hb level of <10g/dL, and a serum creatinine of 2.0 to 6.0mg/dL. They were randomized into two target Hb groups: 161 to high Hb (11.0-13.0g/dL) to receive darbepoetin alfa and low Hb to 160 (9.0-11.0g/dL) to receive recombinant erythropoietin. The study lasted 48weeks. Of 154 and 153 patients with adverse events, cardiovascular adverse events developed in 42 and 51 patients in the high and low Hb groups, respectively, with no significant difference in the incidence. All quality of life scores improved in the high Hb group and vitality improved significantly more with high Hb (P=0.025). The left ventricular mass index (LVMI) remained stable in the low Hb group, but there was a significant decrease in LVMI in the high group (P<0.001). There were no safety concerns with targeting a higher Hb level during the 48weeks of this study. Patients with a higher Hb target had comparatively better outcomes with respect to quality of life and LVMI.
Maintaining high hemoglobin levels improved the left ventricular mass index and quality of life scores in pre-dialysis Japanese chronic kidney disease patients
Clinical and Experimental Nephrology. 2010;14((1):):28-35.
BACKGROUND Anemia is common among patients with chronic kidney disease (CKD). The introduction of erythropoietin treatment has changed anemia management, but the therapeutic hemoglobin (Hb) target is still under debate, and clinical evidence for its effect on cardiac functions and QOL is sparse. METHODS A 16-week dose-response study and a 32-week follow-Up study were combined. After correcting anemia of less than 10 g/dl in pre-dialysis Japanese CKD patients, a higher Hb target (12-13 g/dl) by darbepoetin alfa (DPO) was compared with the conventional Hb target by epoetin alfa (EPO). Outcomes were anemia correction, management of the left ventricular mass index (LVMI) and QOL scores. RESULTS No significant difference was seen in Hb at baseline and week 16, but a significant difference was recorded at week 34 (12. 34 +/- 0. 93 g/dl for DPO and 10. 43 +/- 0. 90 g/dl for EPO). In both groups, LVMI decreased similarly until week 16, but the decrease of EPO was retarded, and a significant difference between LVMI was seen only in DPO at week 34 (100. 7 +/- 16. 6 g/m(2) for DPO and 110. 9 +/- 25. 2 g/m(2) for EPO). Relationships between Hb and LVMI change at week 34 were examined by stratifying Hb into four groups (Hb <10 g/dl, 10 g/dl < or = Hb <11 g/dl, 11 g/dl < or = Hb <12 g/dl and 12 g/dl < or = Hb), and a decrease of LVMI was prominent in the 12 g/dl < or = Hb group. Correction of anemia to 11 g/dl or more led to improved QOL scores. No safety difference was observed among the treatments. CONCLUSIONS Targeting a higher Hb around 12 g/dl was more beneficial than targeting conventional Hb in terms of reduction of LVMI and QOL. Further studies to determine the appropriate Hb target are necessary.
Effects of nafamostat mesilate and minimal-dose aprotinin on blood-foreign surface interactions in cardiopulmonary bypass
The Annals of Thoracic Surgery. 2004;77((2):):644-50.
BACKGROUND The pharmacological inhibition of blood-foreign surface interactions is an attractive strategy for reducing the morbidity associated with cardiopulmonary bypass. We compared the inhibitory effects of nafamostat mesilate (a broad-spectrum synthetic protease inhibitor) and minimal-dose aprotinin on blood-surface interactions in clinical cardiopulmonary bypass. METHODS Eighteen patients undergoing coronary surgery were divided into three groups: (1) the control group (heparin, 4 mg/kg; n = 6), (2) the nafamostat mesilate group (heparin plus nafamostat, 0. 2 mg/kg bolus followed by 2. 0 mg/kg/h during cardiopulmonary bypass; n = 6), and (3) the aprotinin group (heparin plus aprotinin, 2. 0 x 10(4) KIU/kg; n = 6). Platelet count, platelet aggregation, beta-thromboglobulin, prothrombin fragment F1. 2, thrombin-antithrombin complex, plasminogen activator inhibitor-1, alpha2-plasmin inhibitor-plasmin complex, D-dimer, neutrophil elastase, and interleukin-6 were measured before, during, and after bypass. Bleeding times and blood loss were recorded. RESULTS There were no significant differences between groups in platelet count, beta-thromboglobulin, plasminogen activator inhibitor-1, interleukin-6, bleeding times, or blood loss. Platelet aggregation was better preserved at 12 hours after surgery in the nafamostat and aprotinin groups than in the control group. Prothrombin fragment F1. 2, thrombin-antithrombin complex and neutrophil elastase levels were significantly reduced by aprotinin, but not by nafamostat as compared with the control group. The alpha2-plasmin inhibitor-plasmin complex and D-dimer were significantly lower with either of the drugs. Aprotinin showed better control of D-dimer than did nafamostat. CONCLUSIONS Nafamostat mesilate fails to reduce thrombin formation and neutrophil elastase release, whereas minimal-dose aprotinin inhibits both. Neither nafamostat nor aprotinin inhibits platelet activation. Nafamostat reduces fibrinolysis during cardiopulmonary bypass, although its effect is not as potent as aprotinin.
Application of cryoprecipitate as a hematostatic glue
Journal of Cardiovascular Surgery. 1998;39((5):):609-12.
BACKGROUND The effectiveness of cryoprecipitate, harvested from a patient's own fresh frozen plasma, for use in cardiac surgery as a hematostatic glue was studied in 32 randomized elective adult cardiac surgery patients from January 1993 to July 1994. MATERIALS AND METHODS Patients from the Toho Sakura Hospital were randomly allocated to two groups: Group 1 (n=11) received conventional fibrin glue presently available in our institution; while Group 2 (n=21) received autologous cryoprecipitate as a hematostatic glue. Surgical procedures broken down by group were as follows: Group 1: 4 CABG, 5 valvular surgeries and 2 other. Group 2: 11 CABG, 6 valvular surgery, 4 other. We preserved the patient's own blood and stored pure red cell and fresh frozen plasma (FFP). Cryoprecipitate was prepared from the FFP and preserved until required. RESULTS Cryoprecipitate had a 5-fold increase in fibrinogen activity (1190+/-311 mg/dl vs 238+/-34 mg/dl p<0.001), a 10-fold increase in factor VIII activity (362+/-219% vs 34+/-11%, p=0.001), and 4.5-fold increase in factor XIII activity (538+/-213% vs 119+/-50%, p<0.001), compared to serum. The amount of bleeding postoperatively was slightly lower in the cryoprecipitate glue group compared to the conventional glue group, but this was not significantly different. CONCLUSIONS We conclude that autologous samples of human cryoprecipitate prepared from a patient's own FFP had a strong hematostatic effect compared to conventional fibrin glue and was a very valuable hematostatic agent during cardiac surgery.
Effect of low-dose aprotinin on coagulation and fibrinolysis in cardiopulmonary bypass
Annals of Thoracic Surgery. 1993;55((5):):1205-9.
To study the effect of low-dose aprotinin on hemostasis in patients undergoing cardiopulmonary bypass (CPB) for coronary artery bypass operations and to elucidate the mechanism of aprotinin action, we randomized 14 of 27 patients to receive 30,000 KIU/kg aprotinin in the CPB priming volume and 7,500 KIU/kg aprotinin intravenously each hour during CPB (1 patient was excluded from the aprotinin group because of protamine shock). Intraoperative and postoperative blood loss was significantly reduced in the aprotinin group. Antithrombin III level was significantly decreased, and the levels of thrombin-antithrombin III complexes were significantly increased during CPB in both groups, indicating activation of the clotting system. The marked increase in fibrin(ogen) degradation products during CPB in the control group, indicating enhanced fibrinolytic activity, was significantly reduced in the aprotinin group. alpha 2-Plasmin inhibitor was significantly reduced during CPB in the control group. The marked increase in alpha 2-plasmin inhibitor-plasmin complexes in the control group, indicating plasmin activity, was significantly reduced in the aprotinin group. A marked decrease in the platelet count was observed during CPB similarly in both groups. These findings demonstrated that low-dose aprotinin administration was effective in reducing intraoperative and postoperative blood loss and that activation of the clotting system during CPB was not followed by hyperfibrinolysis in aprotinin-treated patients. The improved hemostasis is mainly attributable to the prevention of hyperfibrinolysis during CPB.
Subcutaneous use of erythropoietin in heart surgery
Annals of Thoracic Surgery. 1992;54((3):):479-83; discussion 483-4.
The effect of subcutaneous administration of recombinant human erythropoietin (rHuEPO) in ameliorating anemia resulting from autologous blood donation was compared with intravenous administration of rHuEPO. Forty patients undergoing coronary artery bypass procedures were divided into three groups. Group I (12 patients) received intravenous administration of rHuEPO (100 U.kg-1.day-1) and intravenous iron preparations for 14 days before operation; group II (14 patients) had subcutaneous administration of rHuEPO (600 U/kg) on preoperative days 14 and 7 and oral iron preparations for 14 days; and group III (14 patients) received oral iron preparations alone and served as the controls. Each patient predonated 800 mL of blood in the 2 weeks before operation. The reticulocyte count increased significantly in groups I and II (p less than 0.01), but little in group III. The hemoglobin level just before operation was higher in groups I (p less than 0.01) and II (p less than 0.05) compared with group III. Four patients (29%) in group III required homologous blood transfusion versus none in groups I and II (p less than 0.05). Subcutaneous administration of rHuEPO once a week was as effective as daily intravenous administration. Preoperative autologous blood donation can be performed over a short period on an outpatient basis with subcutaneous administration of rHuEPO.