Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD.
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).


CONCLUSIONS
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.
Levin
Adeera
A
University of British Columbia, St Paul's Hospital, Vancouver, British Columbia, Canada. alevin@providencehealth.bc.ca
Djurdjev
Ognjenka
O
Thompson
Christopher
C
Barrett
Brendan
B
Ethier
Jean
J
Carlisle
Euan
E
Barre
Paul
P
Magner
Peter
P
Muirhead
Norman
N
Tobe
Sheldon
S
Tam
Paul
P
Wadgymar
Jose Arturo
JA
Kappel
Joanne
J
Holland
David
D
Pichette
Vincent
V
Shoker
Ahmed
A
Soltys
George
G
Verrelli
Mauro
M
Singer
Joel
J
D000328:Adult; D000368:Aged; D000740:Anemia / Q000188:drug therapy / Q000517:prevention & control; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use; D002118:Calcium / Q000097:blood; D002170:Canada; D002908:Chronic Disease; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D006454:Hemoglobins / Q000032:analysis*; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000209:etiology / Q000517:prevention & control*; D007674:Kidney Diseases / Q000150:complications* / Q000628:therapy; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009929:Organ Size / Q000187:drug effects; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000097:blood; D011994:Recombinant Proteins; D006435:Renal Dialysis; D016037:Single-Blind Method; D017211:Treatment Failure; D014463:Ultrasonography
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D006454:Hemoglobins; D008055:Lipids; D010281:Parathyroid Hormone; D010710:Phosphates; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; D002118:Calcium