Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis
The New England journal of medicine. 2020;382(7):622-631
BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m(2) of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).
Effect of early correction of anemia on the progression of CKD
Amreican Journal of Kidney Diseases. 2006;47((5):):738-50.
BACKGROUND This study is designed to assess the effect of early and complete correction of anemia by using recombinant human erythropoietin (epoetin) alfa on the progression of chronic kidney disease (CKD). METHODS Patients were randomly assigned to achieve high (13 to 15 g/dL [130 to 150 g/L]) or low (11 to 12 g/dL [110 to 120 g/L]) hemoglobin-level targets during 4 months of stabilization, followed by 36 months of maintenance. Glomerular filtration rate (GFR) decrease was measured by using iohexol clearance. Quality of life, nutrition, and safety also were monitored. RESULTS Because of labeling changes for subcutaneous administration of epoetin alfa (Eprex; Johnson and Johnson, Schaffhausen, Switzerland), the study was terminated prematurely. There were 195 patients enrolled in each group; 108 high-hemoglobin and 133 low-hemoglobin patients entered the maintenance phase. Mean maintenance duration was 7. 4 months for the high-hemoglobin group and 8. 3 months for the low-hemoglobin group. GFR decrease was numerically, but not statistically significantly, lower with the high-hemoglobin group (0. 058 versus 0. 081 mL/min/1. 73 m2/mo [< 0. 01 mL/s/1. 73 m2/mo]). Physical quality-of-life measures showed trends (Role-Physical, P = 0. 055; Physical Function, P = 0. 083) or statistically significant improvement (Vitality, P = 0. 042) with high hemoglobin levels at the end of the stabilization phase. Adverse events were similar between groups. Cardiovascular adverse events occurred in 25% of the high-hemoglobin and 18% of the low-hemoglobin patients (P = 0. 137). Neither epoetin dosage nor hemoglobin level was associated with cardiovascular adverse events or death. CONCLUSION These data suggest that normalization of hemoglobin levels in patients with CKD is safe. Longer duration studies are needed to clarify efficacy benefits with high hemoglobin levels.
Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD
American Journal of Kidney Diseases. 2005;46((5):):799-811.
BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSION 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.
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
Journal of the American Society of Nephrology. 2004;15((1):):148-56.
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.
Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy
Kidney International. 2000;58((3):):1325-35.
BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.