Protamine dosing in cardiac surgery: method is key

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.

This limitation is further underscored by the sample size calculation, which was based on detecting a 10% difference in ACT, a threshold whose clinical relevance is debatable. The authors justify this 10% difference by citing a study comparing ACT with anti-Xa activity in vascular surgery patients (11), a setting with lower heparin levels and no outcome data that is not directly generalizable to the high-dose heparin conditions of CPB in cardiac surgery. Given a weak correlation between ACT and true heparin plasma concentration, the variability of the ACT measurements with reasonable re-test reliability (7) but substantial inter-device variability depending on the measurement methodology (12), small ACT differences are difficult to interpret in a clinically meaningful way. While the study was sufficiently powered to detect such small differences, the absence of a statistically significant effect even at this level suggests that differences large enough to prompt additional protamine administration are unlikely to exist. Thus, the primary concern is not insufficient statistical power, but rather the limited clinical interpretability of small ACT differences, given the weak correlation between ACT and true heparin plasma concentration, the inherent biological and device-related variability of ACT measurements, and the lack of association with clinically relevant outcomes. Accordingly, from a clinical perspective, it would be more meaningful to base the sample size calculation on a patient-centered outcome, such as bleeding, transfusion requirements, or the need for additional protamine administration, as only more pronounced deviations in coagulation parameters would be expected to meaningfully alter anticoagulation management.

Concerning the secondary outcome, Jain et al. found that the fixed-dose strategy, using an initial dose of 250 mg protamine, led to a significantly lower total protamine administration compared to the 1:1 ratio strategy. However, this finding was mathematically inevitable due to the study’s design: because only patients receiving ≥27,500 U of heparin were included, those in the 1:1 ratio strategy group were guaranteed to receive at least 275 mg of protamine, which is higher than the 250 mg starting dose in the fixed-dose strategy group. Consequently, the study, although unintended, effectively compared a ~0.8 ratio (fixed-dose strategy group) against a 1.0 ratio (1:1 ratio strategy group). While, this confirms that a ~0.8 ratio is adequate for initial reversal in low-risk patients, the “reduced drug use” was a pre-determined result of the protocol rather than a clinical discovery.

Beyond methodological considerations, it is also important to align current guidelines recommendations. The 2024 EACTS/EACTAIC Patient Blood Management (PBM) guidelines advocate for individualized heparin neutralization with a protamine-to-heparin dosing ratio <1.0 to avoid overdosing and reduce bleeding complications (13), whereas Jain et al. adopt a pragmatic fixed-dose approach rather than the more tailored titration-based approach now advocated.

Finally, important coagulation-related data are incomplete. Notably, the use of cell salvage blood is not reported. While heparin may be adequately washed-out from salvaged blood through cell saving devices (14), transfusion of cell salvage blood represents a potential confounder for postoperative bleeding and transfusion needs (15,16).

Overall, the study of Jain et al. (1) suggests that many centers may be able to reduce overall protamine use. However, variability in protamine vial concentrations across institutions (e.g., 7,000 U per vial in our hospital) limit the generalizability of these findings, and reduction in “vials used” cannot be directly extrapolated across different practice settings.

Essentially, the results do not justify a universal shift toward fixed-dose protamine administration. Methodological limitations, most notably the focus on ACT values post-protamine, a sample size calculation based on low-range heparin ACT, and the focus on a relatively low-risk patient population (excluding scenarios such as prolonged CPB duration, repeated heparin dosing, endocarditis, aortic dissection, or deep hypothermic circulatory arrest) necessitate a cautious interpretation.

Individualized protamine titration, preferably guided by viscoelastic testing, should remain the gold standard to minimize drug waste and, more importantly, to prevent protamine overdosing (9,13). Future robust randomized controlled trials with clinically relevant outcome measures should focus on this precision-based approach.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article has undergone external peer review.

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0180/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0180/coif). The authors have no conflicts of interest to declare.

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