Phase 2 studies of adenosine cardioplegia.

ABSTRACT

BACKGROUND: Laboratory evidence supports the use of adenosine-supplemented cardioplegia. An initial phase 1 dose-ranging clinical evaluation demonstrated that an adenosine concentration of 15 mumol/L could be safely administered with warm blood cardioplegia and suggested that phase 2 studies were warranted. METHODS AND RESULTS: Two separate double-blind, randomized, placebo-controlled trials were performed in patients undergoing primary, isolated, nonemergent coronary artery bypass graft surgery. Patients were randomized to receive adenosine 15 mumol/L versus placebo in the first study (n = 200) and adenosine 50 or 100 mumol/L versus placebo in the second study (n = 128). Adenosine was infused with both initial and final doses of warm antegrade blood cardioplegia. The data from the 2 trials were combined using the methods of Mantel and Haenszel, and the results of the meta-analysis are presented as the relative risk with their associated 95% confidence intervals (CI). The different study groups were comparable with respect to all preoperative clinical characteristics, angiographic findings, and intraoperative variables. In both trials 1 and 2, no differences were found between groups in the incidence of the individual primary or secondary outcomes. Similarly, when both studies were combined, there was no significant evidence of any consistent treatment benefit (primary death relative risk [RR] = 1.02, 95% CI = 0.06, 16.6; myocardial infarction by CK-MB RR = 0.84, CI = 0.54, 1.31; low output syndrome RR = 1.38, CI = 0.29, 6.42; any of the above RR = 0.98, CI = 0.78, 1.25; secondary Q-wave myocardial infarction RR = 1.30, CI = 0.41, 4.13; myocardial infarction by troponin T RR = 0.7, CI = 0.40, 1.21; inotrope requirement RR = 0.9, CI = 0.46, 1.79; intra-aortic balloon pump requirement RR = 0.6, CI = 0.07, 4.81; P > 0.20). CONCLUSIONS: Despite promising experimental data, adenosine supplementation of warm blood cardioplegia did not demonstrate any statistically significant benefit in patients undergoing elective coronary artery bypass graft surgery. Although sample sizes were relatively small, based on our interim analyses, it is unlikely that increased patient enrollment would reveal any substantive clinical differences between groups.