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obtained in animal research clearly indicated that effectiveness of
EPO treatment reversely proportional to a time elapsed since a
coronary occlusion. In experiments involving the model of perma-
nent coronary occlusion the best result were achieved when EPO
was applied at the time of occlusion. In ischemia-reperfusion
model the most effective results were observed when treatment
was applied no later than at the time of reperfusion, i.e., 30-90 min
from coronary occlusion. In reviewed clinical trials, even if EPO
was injected at the time of PCI, the time from the symptom onset
was sometime as long as 24 h. In the only trial with promising
outcome ( 66 ) the EPO was injected at the time of PCI and the
PCI was done within 6 h of the beginning of symptoms.
We propose that critical therapeutic window for using EPO in
MI patients should be counted from the time of symptom onset,
not from the time of reperfusion. With this proposal in mind we
conducted an experiment to test a hypothesis that design of above
clinical trials made them impossible to succeed ( 68 ). Experiment
was designed to closely replicate one of the clinical trials, REVEAL
( 64, 65 ). In five groups of 2-month old male Wistar rats, the left
descending coronary artery was occluded either by a permanent
(two groups) or a temporary ligature (three groups). In the three
temporary ligature groups the occluding ligature was released 2 h
after occlusion. All animals were sacrificed 24 h after beginning of
occlusion and MI size was measured histologically. Animals from
one of the permanent occlusion groups and one of the temporary
occlusion groups remained untreated. Animals from one of the
temporary occlusion groups received intraperitoneal injection of
3,000 IU/kg of epoetin-alfa immediately after reperfusion.
Another group received the same dose of EPO 4 h after reperfu-
sion, i.e., 6 h after coronary occlusion. The last group (permanent
occlusion) also received the same dose of EPO 6 h after occlusion.
Results of MI size 24 h after occlusion are presented in Fig. 1 . Our
hypothesis had been confirmed: MI size 24 h after coronary occlu-
sion was 42 ± 2% of the area at risk in untreated animals; it was
reduced by ~50% (19 ± 2% of the AAR, p < 0.0001) only in the
group that was treated at the time of reperfusion; MI size in groups
in which treatment was delayed by 4 h after reperfusion or by 6 h
after permanent occlusion was not different from untreated
animals.
1.3
Conclusion
Comparison of experimental data with design of several completed
to date clinical trials clearly suggests that failure of these trials to
improve clinical outcome by using erythropoietin in the acute
phase of MI might be related to design of clinical trials. Experimental
animal data definitely indicated that therapeutic window for eryth-
ropoietin is narrow and dose-dependent. In the doses that substan-
tially exceed customary therapeutic doses for erythropoietin, the
window between coronary occlusion and EPO injection could not
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