In a randomized controlled trial, Jain et al. (1) demonstrated that administration of a fixed 250 mg dose of protamine following cardiopulmonary bypass (CPB) resulted in lower total protamine dose compared with the conventional dosing strategy based on a 1:1 heparin-protamine ratio, without differences in post-protamine activated clotting time (ACT) after initial protamine administration (primary outcome). Approximately 30% of all patients in both groups required additional protamine and among these, ca. 40% exhibited post-protamine ACT values exceeding 20% of baseline after the initial protamine dose. In addition, no differences were observed in the cumulative chest tube drainage 24 h after surgery.

Despite the widespread use of protamine for heparin reversal in cardiac surgery since decades (2), well-designed randomized controlled trials addressing optimal dosing strategies remain limited (3,4). Against this background, the study of Jain et al. provides important insights into this field. Indeed, the authors are to be commended for conducting an investigator-initiated trial in this clinically vital area, which often lacks the commercial incentives typical of industry-sponsored research. The observed reduction in protamine dose, and consequently the number of vials used, is highly pertinent, particularly in the context of pharmaceutical stewardship and ongoing drug supply constraints. However, the method relied upon to assess the adequacy of heparin reversal after CPB, and which formed the basis of the study design, merits a cautious interpretation.

The authors used the ACT to assess the adequacy of heparin reversal after initial protamine administration following separation from CPB. ACT measurements, however, are subject to considerable variability, including the individual sensitivity to heparin, hemodilution, antithrombin levels, preoperative drug regimens, and also variability in ACT measurement devices (5–7). Moreover, other methods like the activated partial thromboplastin time, viscoelastic tests, and heparin essays are more sensitive for detecting residual heparin anticoagulation than ACT (8). Across studies comparing different protamine dosing strategies, post-protamine ACT values are often similar, whereas substantial differences may exist in administered heparin and protamine doses, as well as rotational thromboelastometry (ROTEM) values (9,10). These limitations render ACT measurements unreliable for monitoring of normalization of coagulation after protamine administration or for identifying patients who require additional protamine. Although the authors acknowledge potential limitations of the ACT method (as measured with the Hemochron Signature Elite analyzer), they do not address its appropriateness as the primary modality for assessing heparin reversal.