impact of prophylactic protamine administration following atrial fibrillation ablation on vascular and pericardial complications

Background Protamine is frequently used following atrial fibrillation (AF) ablation to partially reverse the effects of heparin, but its impact on post-procedural complications remains unclear. Purpose To assess whether routine protamine administration after AF ablation reduces vascular and pericardial complications and to evaluate its association with post-procedural hypotension. Methods We retrospectively analyzed all pulmonary vein isolation (PVI) procedures from January 2019 to June 2025, including combined PVI + left atrial appendage occlusion cases. Data were extracted from an institutional registry with complications adjudicated from structured documentation and full-text review. Protamine was administered for heparin reversal; all cases used a continuous heparin infusion titrated to a goal ACT >350 seconds. Cases where adverse events occurred prior to case conclusion (i.e. situations where protamine may have been given reactively rather than prophylactically; n=21) were excluded. Outcomes included non-pericardial bleeding (retroperitoneal bleed, access-site hematoma, pseudoaneurysm), pericardial effusion detected after the procedure, and hypotension reported after protamine administration. Logistic regression models were performed unadjusted and adjusted for age >60 years, sex, sheath size, and closure type (suture vs vascular device). Sheath size was approximated by era: procedures before February 2024 used smaller sheaths (≤9 Fr, radiofrequency), and those after used larger sheaths (≥13 Fr, pulse field ablation). Results Among 11,668 ablation procedures, 9,390 (80.3%) received protamine and 2,278 (19.5%) did not. The median protamine dose was 28 mg (IQR 15–30 mg). Baseline characteristics were similar (mean age 66.3 ± 9.9 vs 67.2 ± 10.0 years; 31.7% vs 32.2% female, p= 0.763). Closure with suture was more common in the protamine group (29.9% vs 20.5%, p=0.064). Event rates were low, and protamine use was not associated with worse outcomes. Pericardial effusion occurred in 0.19% with protamine vs 0.35% without (adjusted OR 0.54, 95% CI 0.23–1.26, p=0.153). Hypotension was infrequent (0.06% vs 0.09%, adjusted OR 0.70, 95% CI 0.14–3.50, p=0.663). Extramediastinal bleeding occurred in 0.35% of both groups (adjusted OR 1.04, 95% CI 0.48–2.26, p=0.922); this included retroperitoneal bleeds (0.05% vs 0.04%, p=0.984), femoral pseudoaneurysms (0.06% vs 0.13%, p=0.873), and access-site hematomas (0.23% vs 0.18%, p=0.328) (Figure 1). No cases of protamine-related anaphylaxis were observed. Conclusions In a registry of >11,000 AF ablations, protamine administration was not associated with reduced extramediastinal bleeding, pericardial effusion, or hypotension. Overall complication rates were low regardless of prophylactic reversal strategy, and no allergic reactions were observed. These findings suggest routine protamine reversal may not substantially impact periprocedural outcomes.