Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Recombinant human erythropoietin treatment in pre-dialysis patients. A double-blind placebo-controlled trial. Early intervention with recombinant human erythropoietin therapy. Analysis of heart morphology and function following erythropoietin treatment of anemic dialysis patients. Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac disease. Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Effect of erythropoietin treatment on physical exercise capacity and on renal function in predialytic uremic patients. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Morbidity and mortality in hemodialysis patients with and without erythropoietin treatment: a controlled study. Non-cardiac benefits of human recombinant erythropoietin in end stage renal failure and anaemia. Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. Safety and efficacy of erythropoietin in children with chronic renal failure. Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD. Effects of early and late intervention with epoetin alpha on left ventricular mass among patients with chronic kidney disease (stage 3 or 4): results of a randomized clinical trial. Blood pressure in hemodialysis patients during amelioration of anemia with erythropoietin. A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients. Normalization of hematocrit in hemodialysis patients with cardiac disease does not increase blood pressure. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. The use of recombinant human erythropoietin in the correction of anemia in predialysis patients and its effect on renal function: a double-blind, placebo-controlled trial.
Therapy with human recombinant erythropoietin (EPO) has been accepted as effective for renal anemia in dialysis patients. However, studies in rats have shown that correcting anemia with EPO may affect the progression of renal dysfunction. In humans, however, the effect of EPO on residual renal function is a matter of controversy. We, therefore, investigated whether the long-term administration of EPO to predialysis patients influences residual renal function. Anemic patients at the predialysis stage with a serum creatinine (Cr) concentration ranging from 2 to 4 (average 2.9) mg/dl and a hematocrit (Ht) of less than 30% were randomly assigned to two groups which consisted of anemic patients not treated with EPO (group I, untreated anemic controls, n = 31) and anemic patients treated with EPO (group II, treated anemics, n = 42). Patients with nonsevere or moderate anemia (Ht > 30%) with a Cr ranging from 2 to 4 (average 2.6) mg/dl were also recruited as nonanemic controls (group III, untreated nonanemic controls, n = 35). Blood pressure was controlled to the same degree among the three groups by combined treatment with calcium antagonists and angiotensin-converting enzyme inhibitors. All patients were kept strictly on a low-protein (0.6 g/kg/day) and a low-salt (7 g/day) diet. The degree of control of dietary protein and blood pressure and the frequency of angiotensin-converting enzyme inhibitor administration were comparable among the three groups. The primary end point for each patient was a doubling of the baseline Cr which yielded cumulative renal survival rates which were plotted against time. Ht rose significantly from 27.0+/-2.3 to 32.1+/-3.2% in group II (n = 42, p < 0.001) with a rate of increase of 0.4+/-0.06%/week. However, it declined from 27.9+/-1.8 to 25.3+/-1.9% in group I (n = 31, p < 0.001) and from 35.9+/-3.5 to 32.2+/-3.9% in group III (n = 35, p < 0.001). Cr doubled in 26 patients (84%) in group I as compared with 22 (52%) in group II and 21 (60%) in group III. The cumulative renal survival rates in groups II and III were significantly better than that in group I: p = 0.0003 (group I vs. group II) and p = 0.0024 (group I vs. group III). However, there was no difference in the renal survival rate between groups II and III (p = 0.3111). The better survival rate obtained in group II was attributable to the better survival rate for the nondiabetic patients in this group. The present study suggests that anemia, per se, is a factor in the progression of end-stage renal failure and that reversal of anemia by EPO can retard the progression of renal failure, especially in nondiabetic patients, provided that blood pressure control, rate of increase in Ht, and dietary protein restriction are appropriate. Hemoglobin levels below 10 g/dL lead to left ventricular (LV) hypertrophy, LV dilation, a lower quality of life, higher cardiac morbidity, and a higher mortality rate in end-stage renal disease. The benefits and risks of normalizing hemoglobin levels in hemodialysis patients without symptomatic cardiac disease are unknown.
                One hundred forty-six hemodialysis patients with either concentric LV hypertrophy or LV dilation were randomly assigned to receive doses of epoetin alpha designed to achieve hemoglobin levels of 10 or 13.5 g/dL. The study duration was 48 weeks. The primary outcomes were the change in LV mass index in those with concentric LV hypertrophy and the change in cavity volume index in those with LV dilation.
                In patients with concentric LV hypertrophy, the changes in LV mass index were similar in the normal and low target hemoglobin groups. The changes in cavity volume index were similar in both targets in the LV dilation group. Treatment-received analysis of the concentric LV hypertrophy group showed no correlation between the change in mass index and a correlation between the change in LV volume index and mean hemoglobin level achieved (8 mL/m2 per 1 g/dL hemoglobin decrement, P = 0.009). Mean hemoglobin levels and the changes in LV mass and cavity volume index were not correlated in patients with LV dilation. Normalization of hemoglobin led to improvements in fatigue (P = 0.009), depression (P = 0.02), and relationships (P = 0.004).
                Normalization of hemoglobin does not lead to regression of established concentric LV hypertrophy or LV dilation. It may, however, prevent the development of LV dilation, and it leads to improved quality of life. To determine the efficacy and safety of recombinant human erythropoietin (r-HuEPO) in predialysis renal patients.
                Randomized, double-blind, placebo-controlled trial for 8 weeks.
                Inpatient and outpatient facility in the Clinical Research Center of a university-based hospital.
                Fourteen adult subjects with renal insufficiency (mean serum creatinine, 473 mumol/L +/- 61 [6.2 +/- 0.8 mg/dL]) and anemia (mean hematocrit, 0.27 +/- 0.01).
                Recombinant human erythropoietin, 50, 100, or 150 IU/kg body weight or placebo given intravenously three times per week.
                Subjects who received active r-HuEPO showed a dose-dependent rise in hematocrit; mean hematocrit increased 41% from 0.27 +/- 0.01 to 0.38 +/- 0.01. At the same time, erythrocyte mass rose 43% from 13.7 +/- 0.6 mL/kg in the baseline state to 19.6 +/- 1.0 mL/kg after treatment. Maximal oxygen consumption during exercise increased 9% from 16.0 mL/min.kg +/- 1.8 to 17.5 mL/min.kg +/- 1.9.
                Recombinant human erythropoietin is effective and safe in ameliorating the anemia of pre-dialysis patients. nan In a two-way study, we treated renal anemia in chronic hemodialysis patients with recombinant human erythropoietin (rh-EPO) and followed heart morphology and function dynamics by echocardiography. Thirty-eight patients were randomly divided in two equal groups: the therapy group, treated with rh-EPO for 24 months, and the control group, not treated during the first 12 months and treated with rh-EPO during the second 12 months. Anemia was corrected, and hematocrit was maintained between 30 and 35 vol% by subcutaneous rh-EPO administration. Echocardiographic assessment was performed at the end of the untreated control phase and was repeated after 12 months of rh-EPO treatment in the control group and after 12 and 24 months of treatment in the therapy group. The results revealed significant morphologic, hemodynamic, and eventually functional changes. After 12 months of rh-EPO treatment, the end-diastolic volume (EDV) decreased from 135.8 +/- 23.7 to 109.8 +/- 25.3 ml, p < 0.001; stroke volume (SV) from 91.9 +/- 17.6 to 71.3 +/- 12.4 ml, p < 0.001; left ventricular mass-Devereux (LVMD) from 297.2 +/- 57.8 to 218.0 +/- 50.4 g, p < 0.01; cardiac output (CO) from 7,279 +/- 1,932 to 5,711 +/- 1,276 ml/min, p < 0.002; total peripheral resistance (TPR) rose from 1,330 +/- 390 to 1,707 +/- 373 dynes x s/cm5, p < 0.007. After 24 months, LVMD decreased further from 224.6 +/- 43.1 to 195.7 +/- 46.3 g, p < 0.004. The relaxation time index (RTI) decreased from 64.7 +/- 20.4 to 52.4 +/- 18.0 ms, p < 0.045, suggesting improved diastolic function.(ABSTRACT TRUNCATED AT 250 WORDS) Hypertension is a recognized complication of partial correction of anemia with recombinant human erythropoietin (epoetin) in hemodialysis patients. We used interdialytic ambulatory blood pressure (ABP) monitoring to study the effects of partially corrected anemia versus normal hematocrit (hct) on BP in hemodialysis patients.
                Repeated interdialytic ABP monitoring was performed for up to one year in 28 chronic hemodialysis patients with cardiac disease who were randomized to achieve and maintain normal hct levels (42 +/- 3%, group A) or anemic hct levels (30 +/- 3%, group B) with epoetin. Routine BP measurements obtained at dialysis treatments were also evaluated.
                Mean hct levels were 30.7 +/- 0.7% in group A and 30.6 +/- 0.7% in group B at baseline, then 39.3 +/- 1.2% (group A) and 33.5 +/- 0.6% (group B) at four months, and 42.0 +/- 1.1% (group A) and 30.4 +/- 1.0% (group B) at 12 months. Baseline ABP and routine dialysis unit BP levels were not different between the groups. At 2, 4, 8, and 12 months of follow-up, there were no statistically significant differences in any BP parameters between groups or increases in any BP parameters in either group A or group B patients compared with baseline. At 12 months, the mean nighttime diastolic BP (DBP) in group A patients was slightly but significantly lower than the mean daytime DBP (daytime DBP 76.6 +/- 1.9 mm Hg vs. nighttime DBP 72.9 +/- 2.1 mm Hg, P < 0.05). The mean daytime and nighttime BPs were not different from each other at two, four, and eight months in group A or at any time in group B, and in both groups, most patients had little diurnal change in BP.
                Correction of hct to normal with epoetin in chronic hemodialysis patients with cardiac disease did not cause increased BP as assessed by interdialytic ABP monitoring or by the measurement of routine predialysis and postdialysis BP. There was little diurnal change in systolic or diastolic BP at baseline or after correction of anemia to normal levels, and although mean nighttime DBP was lower than mean daytime DBP at 12 months in group A, the maintenance of normal hct levels did not affect the abnormal diurnal BP pattern seen at moderately anemic hct levels in most patients. Erythropoietin is known to improve outcomes in patients with anemia from chronic renal disease. However, there is uncertainty about the optimal timing of initiation of erythropoietin treatment in predialysis patients with non-severe anemia.
                We conducted a randomized controlled trial of early versus deferred initiation of erythropoietin in nondiabetic predialysis patients with serum creatinine 2 to 6 mg/dL and hemoglobin 9 to 11.6 g/dL. The early treatment arm was immediately started on 50 U/kg/wk of erythropoietin alpha with appropriate titration aiming for hemoglobin of > or =13 g/dL. The deferred treatment arm would start erythropoietin only when hemoglobin decreased to <9 g/dL. The primary end point was a composite of doubling of creatinine, renal replacement, or death.
                Eighty-eight patients were randomized (early treatment N= 45, deferred treatment N= 43) and followed for a median of 22.5 months. During follow-up, 13 versus 23 patients reached the primary end point in the two arms, respectively (log-rank P= 0.0078). The relative hazard for reaching an end point was 0.42 (P= 0.012). Adjusting for baseline serum creatinine, the adjusted relative hazard was 0.37 (P= 0.004), while the risk increased 2.23-fold (P < 0.001) per 1 mg/dL higher creatinine at baseline. The benefit was similar regardless of the baseline hemoglobin and proteinuria. No patients had any severe adverse events.
                Early initiation of erythropoietin in predialysis patients with non-severe anemia significantly slows the progression of renal disease and delays the initiation of renal replacement therapy. Anemia is already present in patients with moderate renal failure and is a major cause of the decline in exercise capacity seen in these patients. We examined the effects of erythropoietin (EPO) treatment in 12 predialytic uremic patients (EPO group: mean age 46 +/- 12 years; 6 men, 6 women) with a mean glomerular filtration rate (GFR) of 10 +/- 4 ml/min x 1.73 m2. These patients were compared to a control group of 8 patients (5 men, 3 women). The observation period was 3 months. The EPO group received 300 U/kg body weight i.v. once a week. The EPO group increased their total hemoglobin (THb) from 323 +/- 89 to 466 +/- 128 g (p less than 0.001) and their hemoglobin concentration from 86 +/- 8 to 117 +/- 11 milligrams (p less than 0.001). Their exercise capacity, measured by a standardized exercise test on a bicycle ergometer, increased from 128 +/- 45 to 147 +/- 57 W (p less than 0.01). The control group did not change their THb (349 +/- 124 and 357 +/- 131 g), hemoglobin (93 +/- 8 and 94 +/- 10 milligrams) or exercise capacity (98 +/- 49 and 101 +/- 50 W) during the observation period. There was a significant correlation between the increase in THb and the increase in exercise capacity in the EPO group (r = 0.81, p less than 0.005). The GFR was unchanged in both groups (EPO group: 10 +/- 4 and 10 +/- 6 ml/min x 1.73 m2; control group: 8 +/- 3 and 8 +/- 3 ml/min x 1.73 m2).(ABSTRACT TRUNCATED AT 250 WORDS) It is unclear whether physiologic hemoglobin targets lead to cardiac benefit in incident hemodialysis patients without symptomatic heart disease and left ventricular dilation. In this randomized, double-blind study, lower (9.5 to 11.5 g/dl) and higher (13.5 to 14.5 g/dl) hemoglobin targets were generated with epoetin alpha over 24 wk and maintained for an additional 72 wk. Major eligibility criteria included recent hemodialysis initiation and absence of symptomatic cardiac disease and left ventricular dilation. The primary outcome measure was left ventricular volume index (LVVI). The study enrolled 596 patients. Mean age, duration of dialysis therapy, baseline predialysis hemoglobin, and LVVI were 50.8 yr, 0.8 yr, 11.0 g/dl, and 69 ml/m2, respectively; 18% had diabetic nephropathy. Mean hemoglobin levels in the higher and lower target groups were 13.3 and 10.9 g/dl, respectively, at 24 wk. Percentage changes in LVVI between baseline and last value were similar (7.6% in the higher and 8.3% in the lower target group) as were the changes in left ventricular mass index (16.8 versus 14.2%). For the secondary outcomes, the only between-group difference was an improved SF-36 Vitality score in the higher versus the lower target group (1.21 versus -2.31; P = 0.036). Overall adverse event rates were similar in both target groups; higher (P < 0.05) rates of skeletal pain, surgery, and dizziness were seen in the lower target group, and headache and cerebrovascular events were seen in the higher target group. Normalization of hemoglobin in incident hemodialysis patients does not have a beneficial effect on cardiac structure, compared with partial correction. The investigators evaluated the impact of recombinant human erythropoietin (r-HuEPO) therapy on health-related quality of life (HRQL) in predialysis chronic renal disease patients with anemia. Eighty-three patients were entered into a randomized, parallel-group, open-label clinical trial with follow-up evaluations over 48 weeks. Forty-three patients were assigned to r-HuEPO treatment, and 40 patients were assigned to an untreated control group. Hematocrit levels were measured at baseline and monthly. HRQL was assessed at baseline and at weeks 16, 32, and 48. The HRQL assessment included measures of physical function, energy, role function, health distress, cognitive function, social function, home management, sexual dysfunction, depression, and life satisfaction. Significant improvements in hematocrit levels were observed in the r-HuEPO-treated group (P < 0.0001), and no changes were seen in the untreated group. Correction of anemia (hematocrit > or = 36) occurred in 79% of r-HuEPO-treated patients and 0% of control patients. Significant improvements in assessments of energy (P < 0.05), physical function (P < 0.05), home management (P < 0.05), social activity (P < 0.05), and cognitive function (P < 0.05) were found for the r-HuEPO-treated group. No changes were observed in the control group, except for a decrease in physical function (P < 0.05). Between-group differences favoring the r-HuEPO-treated group were found for energy (P < 0.05) and physical functioning (P < 0.05). In patients receiving r-HuEPO, significant improvements were seen in hemotocrit levels, and these increases resulted in improvements in HRQL. nan Recombinant human erythropoietin (r-HuEpo) is now available to correct the anaemia of end stage renal failure. The clinical consequences of increasing the haemoglobin concentration in children on dialysis are incompletely documented; a placebo controlled study is essential when assessing subjective changes, for example in appetite or other aspects of quality of life. A single blind, placebo controlled crossover study in 11 children with end stage renal failure was performed to assess the clinical benefits resulting from correction of anaemia. Ten of the 11 children completed 36 weeks of the study and seven completed both 24 week limbs. Subcutaneous administration of r-HuEpo twice a week resulted in an increase in haemoglobin concentration, from 73 to 112 g/l. This was associated with an objective improvement in exercise tolerance, and a subjective improvement in physical performance and health, and better school attendance. No consistent effect was seen on appetite, growth, psychosocial functioning, biochemical control, or peritoneal dialysis efficiency. A small but clinically unimportant increase in systolic and diastolic blood pressure was seen in five children. One child on antihypertensive treatment required an increase in dosage during r-HuEpo while another child required a reduction in treatment. These findings, together with the important cardiac benefits previously described during r-HuEpo treatment, support the use of r-HuEpo in all children with end stage renal failure and anaemia. The purpose of this study was to determine the efficacy of recombinant human erythropoietin (rHuEPO) given subcutaneously three times/week in patients with chronic renal failure and anemia (predialysis).
                Eleven patients with predialysis chronic renal failure participated in a double-blind, placebo-controlled study of subcutaneously administered erythropoietin. For 12 weeks, patients received either rHuEPO 100 mu/kg body weight three times/week subcutananeously or a placebo. After 12 weeks of placebo, patients now also received rHuEPO in a dose up to 150 mu/kg three times/week until target hematocrit was achieved. Throughout the study, blood pressure was monitored closely and blood work was obtained regularly for hemoglobin, hematocrit, reticulocyte count, and iron profile determinations.
                At 12 weeks, the hematocrit of the treated group had risen from 29% +/- 2% to 35% +/- 2% (p less than 0.001). The placebo group baseline hematocrit was 28% +/- 2% and at 12 weeks 26% +/- 2% After 12 weeks of rHuEPO therapy, the hematocrit of the prior placebo group was 32% +/- 2% (p less than 0.001 versus baseline). No significant change in biochemical parameters was noted. Mean blood pressure values were comparable before and after treatment. All protein ultimately required iron supplementation. In two patients, the rate of progression of renal failure appeared to increase as their hematocrit rose and rHuEPO was discontinued.
                It is concluded that rHuEPO given subcutaneously is an effective and safe therapy for patients with chronic renal failure who are anemic and who are not receiving dialysis. A prospective randomized study of the use of recombinant human erythropoietin (rHuEPO) in children with chronic renal disease was conducted to assess dosing requirements and side effects. Forty-four children with chronic renal failure, aged 4 months to 21 years, were studied. Twenty-five patients were pre dialysis, 10 on peritoneal dialysis, and 9 on hemodialysis. Patients received either 150 U/kg per week or 450 U/kg per week divided thrice weekly of rHuEPO for 12 weeks or until target hemoglobin (Hb) was attained. Dose was then adjusted to maintain a normal Hb. Eighty-two percent of patients reached target Hb by 7.9+/-5.6 weeks (mean+/-SD); 95% of patients in the high-dose group and 66% in the low-dose group reached target Hb within 12 weeks. The overall median rHuEPO dose at target Hb was 150 U/kg per week. Hemodialysis patients tended to require more rHuEPO to maintain a normal Hb (median 250 U/kg per week). Transfusion requirements and panel-reactive antibody levels decreased during the 12 weeks. Iron deficiency and/or hypertension occurred in 30% of children. In conclusion, rHuEPO at 150 U/kg per week is safe and effective in treating anemia in children with chronic renal disease. This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data.
                One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12.0 to 14.0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9.0 +/- 0.5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9.0 to 10.5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months.
                One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0.48 mL/s; range, 12 to 55 mL/min [0.20 to 0.92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5.21 +/- 30.3 g/m2 in the control/delayed treatment group versus 0.37 +/- 25.0 g/m2 in the treatment group. Absolute mean difference between groups was 4.85 g/m2 (95% confidence interval, -4.0 to 13.7; P = 0.28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12.75 g/dL (127.5 g/L in treatment group versus 11.46 g/dL [114.6 g/L] in control/delayed treatment group; P = 0.0001). LV growth occurred in 20.1% in the treatment group versus 31% in the control/delayed treatment group (P = 0.136). In patients with a stable Hgb level, mean LVMI did not change (-0.25 +/- 26.7 g/m2), but it increased in those with decreasing Hgb levels (19.3 +/- 28.2 g/m2; P = 0.002).
                This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed. It is not known whether prevention of anemia among patients with chronic kidney disease would affect the development or progression of left ventricular (LV) hypertrophy. A randomized controlled trial was performed with 155 patients with chronic kidney disease (creatinine clearance, 15 to 50 ml/min), with entry hemoglobin concentrations ([Hb]) of 110 to 120 g/L (female patients) or 110 to 130 g/L (male patients). Patients were monitored for 2 yr or until they required dialysis; the patients were randomized to receive epoetin alpha as necessary to maintain [Hb] between 120 and 130 g/L (group A) or between 90 and 100 g/L (group B). [Hb] increased for group A (from 112 +/- 9 to 121 +/- 14 g/L, mean +/- SD) and decreased for group B (from 112 +/- 8 to 108 +/- 13 g/L) (P < 0.001, group A versus group B). On an intent-to-treat analysis, the changes in LV mass index for the groups during the 2-yr period were not significantly different (2.5 +/- 20 g/m(2) for group A versus 4.5 +/- 20 g/m(2) for group B, P = NS). There was no significant difference between the groups in 2-yr mean unadjusted systolic BP (141 +/- 14 versus 138 +/- 13 mmHg) or diastolic BP (80 +/- 6 versus 79 +/- 7 mmHg). The decline in renal function in 2 yr, as assessed with nuclear estimations of GFR, also did not differ significantly between the groups (8 +/- 9 versus 6 +/- 8 ml/min per 1.73 m(2)). In conclusion, maintenance of [Hb] above 120 g/L, compared with 90 to 100 g/L, had similar effects on the LV mass index and did not clearly affect the development or progression of LV hypertrophy. The maintenance of [Hb] above 100 g/L for many patients in group B might have been attributable to the relative preservation of renal function. This study analyzed blood pressure in hemodialysis patients treated with epoetin beta in multicenter trials. Antihypertensive drugs were prescribed as usual. Placebo-controlled trials compared epoetin (100 to 150 U/kg; N = 151) with placebo (N = 78) for 82 days. Hemoglobin (108 +/- 18 versus 75 +/- 14 g/L) (mean +/- SD) and diastolic blood pressure (84 +/- 14 versus 78 +/- 15 mm Hg) were greater (P less than 0.05) after epoetin. Clinically important increases in blood pressure (increases in diastolic blood pressure greater than or equal to 10 mm Hg and/or drug therapy) were more frequent with epoetin (58 versus 37%; P = 0.005). A dose-response trial compared epoetin, 25 U/kg (N = 42), 100 U/kg (N = 40), and 200 U/kg (N = 39) for 138 days. Increases in hemoglobin were dose dependent, but clinically important increases in blood pressure were not. In analyses of all patients treated with epoetin (N = 272), no baseline or final level of hemoglobin, or rate of hemoglobin rise, was a threshold for a rise in blood pressure. Patients requiring antihypertensive drugs or having uncontrolled hypertension (diastolic blood pressure greater than 90 mm Hg) at baseline had decreases in blood pressure (P less than 0.05) with antihypertensive therapy. Thus, compared with placebo, 21% of patients had clinically important increases in blood pressure during amelioration of anemia. The baseline or final levels of hemoglobin, the extent or rate of hemoglobin rise, or uncontrolled hypertension or antihypertensive drug use at baseline were not confirmed as risks. Antihypertensive drug therapy was important for blood pressure control. Partial correction of renal anaemia with erythropoietin improves quality of life (QoL). We aimed to examine if normalization of haemoglobin with epoetin alfa in pre-dialysis and dialysis patients further improves QoL and is safe.
                416 Scandinavian patients with renal anaemia [pre-dialysis, haemodialysis (HD) and peritoneal dialysis patients] were randomized to reach a normal haemoglobin of 135-160 g/l (n=216) or a subnormal haemoglobin of 90-120 g/l (n=200) with or without epoetin alfa. Study duration was 48-76 weeks. QoL was measured using Kidney Disease Questionnaires in 253 Swedish dialysis patients. Safety was examined in all patients.
                QoL improved, measured as a decrease in physical symptoms (P=0.02), fatigue (P=0.05), depression (P=0.01) and frustration (P=0.05) in the Swedish dialysis patients when haemoglobin was normalized. In pre-dialysis patients, diastolic blood pressure was higher in the normal compared with the subnormal haemoglobin group after 48 weeks. However, the progression rate of chronic renal failure was comparable. In the normal haemoglobin group (N-Hb), 51% had at least one serious adverse event compared with 49% in the subnormal haemoglobin group (S-Hb) (P=0.32). The incidence of thrombovascular events and vascular access thrombosis in HD patients did not differ. The mortality rate was 13.4% in the N-Hb group and 13.5% in the S-Hb group (P=0.98). Mortality decreased with increasing mean haemoglobin in both groups.
                Normalization of haemoglobin improved QoL in the subgroup of dialysis patients, appears to be safe and can be considered in many patients with end-stage renal disease. Since the earliest reports of the use of Epoetin alfa in hemodialysis patients, it has been described that Epoetin alfa may exacerbate preexisting hypertension or induce hypertension in End Stage Renal Disease (ESRD) patients not previously hypertensive. We undertook this study to determine if the correction of anemia in ESRD patients with cardiac disease from a hematocrit of 30+/-3% to 42+/-3% with the use of Epoetin alfa would result in increased blood pressure. This study was a substudy of the "Normal hematocrit Study".
                Thirty-one patients were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42+/-3% and patients in Group B were maintained with a hematocrit of 30+/-3% throughout the course of the study. All patients had their blood pressure recorded with a 24 hour ambulatory BP device at study entry and at 28 weeks following randomization when they had achieved their target hematocrit. Pre-dialysis systolic and diastolic BP was also recorded.
                The mean hematocrit increased in Group A from 29.1+/-2.4% to 40.8+/-5.2% after 30 weeks. The hematocrit in Group B remained stable at 30+/-3% throughout the course of the study. There was no difference in mean daytime, mean nighttime or 24 hour systolic or diastolic blood pressure between Groups A and B at either baseline or follow-up. Neither was there a difference in mean pre-dialysis systolic or diastolic BP between Groups A or B at baseline or Follow-up. Four patients in Group A and 4 patients in Group B required an increase in their antihypertensive medication during the course of the study.
                It is possible to increase hematocrit to normal levels in hemodialysis with the administration of Epoetin alfa. The increase in hematocrit from 30+/-3% to 42+/-3% is not associated with increased blood pressure. In patients with end-stage renal disease, anemia develops as a result of erythropoietin deficiency, and recombinant human erythropoietin (epoetin) is prescribed to correct the anemia partially. We examined the risks and benefits of normalizing the hematocrit in patients with cardiac disease who were undergoing hemodialysis.
                We studied 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis: 618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42 percent, and 615 were assigned to receive doses of epoetin sufficient to maintain a hematocrit of 30 percent throughout the study. The median duration of treatment was 14 months. The primary end point was the length of time to death or a first nonfatal myocardial infarction.
                After 29 months, there were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infarctions among those in the low-hematocrit group (risk ratio for the normal-hematocrit group as compared with the low-hematocrit group, 1.3; 95 percent confidence interval, 0.9 to 1.9). Although the difference in event-free survival between the two groups did not reach the prespecified statistical stopping boundary, the study was halted. The causes of death in the two groups were similar. The mortality rates decreased with increasing hematocrit values in both groups. The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group.
                In patients with clinically evident congestive heart failure or ischemic heart disease who are receiving hemodialysis, administration of epoetin to raise their hematocrit to 42 percent is not recommended. Fourteen nondialyzed patients with chronic renal insufficiency (serum creatinine 265 to 972 mumol/L [3.0 to 11.0 mg/dL]) and severe anemia (hematocrit less than 30%) were randomized to receive either recombinant human erythropoietin (r-HuEPO) or a placebo subcutaneously thrice weekly for 12 weeks or until reaching a hematocrit of 38% to 40%. Anemia was significantly ameliorated in the treated patients. No acceleration in the progression of renal failure (1/serum creatinine v time) or change in serum potassium was noted for either the placebo or treated group over the 12-week period. Six of seven treated patients had a significant decrease in serum ferritin and percent transferrin saturation (plasma iron/total iron-binding capacity). This resulted in functional iron deficiency and the requirement for iron supplementation. The average systolic and diastolic blood pressure did not differ significantly between the two groups of patients during the study. Quality of life was improved in all r-HuEPO-treated patients but not in those in the placebo group. This study demonstrates the safety and efficacy of r-HuEPO in the correction of anemia in predialysis patients without adverse effects on renal function over a 12-week period. Improved patient well-being as a result of the correction of anemia resulted in one patient refusing appropriate initiation of dialysis therapy.
There was no significant difference in the risk of death for low (< 120 g/L) versus higher Hb targets (>133 g/L). Lower Hb targets were significantly associated with an increased risk for seizures but a reduced risk of hypertension. In general study quality was poor. There is a need for more adequately powered, well-designed and reported trials. Trials should be pragmatic, focusing on hard end-points (mortality, ESKD, major side effects) or outcomes which were previously not studied adequately (e.g. seizures, quality of life).