Canadian Randomized Trial of Hemoglobin Maintenance to Prevent or Delay Left Ventricular Mass Growth in Patients With CKD

University of British Columbia, St Paul's Hospital, Vancouver, British Columbia, Canada.
American Journal of Kidney Diseases (Impact Factor: 5.9). 12/2005; 46(5):799-811. DOI: 10.1053/j.ajkd.2005.08.007
Source: PubMed


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.

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Available from: Joel Singer, Apr 20, 2015
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    • "The importance of anemia management from the early stages of CKD has been emphasized and several controlled studies have been conducted to determine the reasonable target levels in correcting anemia [11] [12] [13] [14] [15]. However, the optimal target levels for Please cite this article in press as: Akaishi M, et al. "
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    ABSTRACT: Background and purpose To assess effects of long-term anemia management on left ventricular hypertrophy in patients with chronic kidney disease (CKD) not on dialysis, we performed secondary outcome analyses of a randomized controlled study that evaluated effects of anemia management with erythropoiesis stimulating agents in this population. Methods and subjects Subjects [hemoglobin (Hb) < 10.0 g/dL, 2.0 ≤ serum creatinine < 6.0 mg/dL] were randomized either to high Hb (11.0 ≤ target Hb ≤ 13.0 g/dL with darbepoetin alfa), or to low Hb group (9.0 ≤ target Hb ≤ 11.0 g/dL with recombinant human erythropoietin), and followed up to 48 weeks. Data from echocardiographic evaluation and values of neurohumoral factors associated with heart failure were assessed in subjects whose data were evaluable both at the baseline and at the end point. Results The high Hb group achieved target range Hb levels (12.1 ± 1.1 g/dL, at 32 weeks, N = 111), which was significantly higher (p < 0.001) than the low Hb group (N = 95). Though blood pressure and renal function changes were similar between the groups, left ventricular diastolic dimension was significantly decreased only in the high Hb group (p < 0.001), and the change in left ventricular mass index (LVMI) correlated coarsely but significantly with the achieved Hb levels (r = 0.147, p = 0.032). The higher Hb levels were associated with greater reduction in LVMI and left ventricular wall thickness, and the lower Hb levels with the greater increase in human arterial- or brain natriuretic polypeptide levels. Conclusions Anemia correction targeting modestly higher Hb levels better preserves cardiac function in CKD patients not on dialysis.
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    • "Levin et al. have reported the prevalence of LVH in 26.7% of patients with GFR > 50 mL/min, in 30.8% of those with GFR between 25 and 49 mL/min and in 45.2% of patients with severe CKD (GFR <25 mL/min [16], which is more or less in accordance with our findings. High prevalence of increased LVMI in CKD has been repeatedly described [16-18], but the studies are difficult to compare due to different definitions of LVH, different study populations and variations in blood pressure control, including the use of ACE inhibitors and/or ARBs. "
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    • "Cardiovascular disease is prevalent and the most common cause of morbidity and mortality in patients with end-stage renal disease (ESRD) [1]. Even though coronary artery disease and arrhythmia are not uncommon, left ventricular hypertrophy (LVH) is the most frequent cardiovascular manifestation in these patients [2], [3]. LVH is known to be present in more than 70% of incident ESRD patients and increases the risk for cardiac ischemia and congestive heart failure in patients on dialysis [4], [5]. "
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