Clin Res Cardiol (2022).

Optimal protamine-to-heparin dosing ratio prevents bleeding complications in patients undergoing TAVR - a multicenter study
B. Al-Kassou1, K. Piayda2, A. Aksoy1, T. Zeus2, J. Shamekhi1, A. Zietzer1, E. Grube1, J.-M. Sinning3, M. Kelm2, S. Zimmer1, G. Nickenig1, V. Veulemans2, A. Sedaghat1
1Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Bonn; 2Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Düsseldorf, Düsseldorf; 3Innere Medizin III - Kardiologie, St. Vinzenz-Hospital, Köln;

Despite technical and clinical advances, Transcatheter aortic valve replacement (TAVR) is still associated with procedure-related vascular and bleeding complications, that have a significant impact on mortality. A recently published study has shown that protamine administration for heparin reversal after the TAVR procedure resulted in significantly lower rates of serious bleeding events as compared to patients without heparin antagonization. Nevertheless, it must be noted that Protamine also has dose-dependent anticoagulant and thrombotic effects. Therefore, proper protamine dosing is important to avoid serious side effects. However, the optimal protamine-to-heparin dosing ratio to prevent bleeding complications after the TAVR procedure is not known.

The aim of this observational multicenter study was a comparison of different protamine-to-heparin dosing ratios for the prevention of bleeding complications after TAVR. METHODS: Our study cohort included 1348 patients undergoing TAVR, of whom 771 (57.3%) received full antagonization of heparin and 577 (42.8%) received a partial antagonization of heparin with a protamine-to-heparin ratio of 1 to 2. The given dose of protamine was left to the discretion of the operator, who made the decision according to the angiographic presentation of the access site and the patient's individual thrombotic risk. The primary endpoint of the study was a composite of 30-day all-cause mortality, life-threatening as well as major bleeding. The safety end point included VARC-2–defined stroke and myocardial infarction at 30 days.

The mean age of our study population was 81.0 (±6.2) years and 47.9% were of female gender. The baseline characteristics were well balanced between both groups. Full antagonization of heparin resulted in a significantly lower rate of the primary endpoint (5.1%) as compared to patients with a partial heparin reversal (9.9%, p<0.001). This was mainly driven by lower rates of life-threatening and major bleedings in patients with full antagonization of heparin (0.4% vs 1.4%, p=0.05; 2.7% vs 7.8%, p<0.001, respectively), as presented in Figure 1. Moreover, major vascular complications were significantly less frequent in 
patients with full antagonization of heparin (3.1% vs 7.6%, p<0.001). Regarding safety endpoints, there were no significant differences between patients with full and partial antagonization of heparin with comparable rates of stroke (2.1% vs 2.6%, p=0.58) and myocardial infarction (0.4% vs 0.2%, p=0.64). In multivariate analysis, only full antagonization of heparin (OR: 0.24 [95% CI: 0.13 - 0.43], p<0.001) was independently associated with the primary end point.

Full antagonization of heparin with protamine resulted in significantly lower rates of life-threatening and major bleeding complications after TAVR as compared to patients with partial heparin reversal. The occurrence of stroke and myocardial infarction was low and comparable between both groups.