Protamine sulfate is widely used to reverse unfractionated heparin during transfemoral transcatheter aortic valve replacement (TAVR), but the optimal reversal strategy remains uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials and observational studies comparing full heparin reversal (1 mg protamine per 100 units heparin) with partial or no reversal in transfemoral TAVR. The primary outcome was a composite of all-cause mortality, major bleeding, and major vascular complications, defined according to VARC-3 criteria, while secondary outcomes included each component of the composite and stroke. Five studies (two randomized trials, three cohort studies) involving 3,089 patients were included. Full-dose protamine significantly reduced the composite outcome (RR 0.46, 95% CI 0.36–0.60), driven by reductions in major bleeding (RR 0.41, 95% CI 0.28–0.59) and major vascular complications (RR 0.44, 95% CI 0.30–0.65). No excess risk was observed for all-cause mortality (RR 0.94, 95% CI 0.65–1.36) or stroke (RR 0.67, 95% CI 0.40–1.12). Leave-one-out and subgroup analyses confirmed the robustness of these findings, and no evidence of publication bias was identified. In conclusion, full heparin reversal with protamine during TAVR is associated with lower bleeding and vascular complications without increasing thromboembolic risk, supporting its use as a bleeding-avoidance strategy.
Protamine sulfate (PS) is a widely used agent for reversing the anticoagulant effects of unfractionated heparin (UFH), particularly in cardiovascular procedures. During transcatheter aortic valve replacement (TAVR), bleeding and vascular complications remain significant concerns, despite advancements in procedural techniques and the introduction of next-generation valve systems. These complications are strongly associated with increased morbidity, mortality, and prolonged hospital stays, underscoring the need for optimized anticoagulation management strategies.
Routine anticoagulation during TAVR aims to achieve an activated clotting time (ACT) of 250–300 seconds to minimize thromboembolic risks. Protamine is frequently administered at the end of the procedure to reverse UFH before vascular closure, a practice standard in cardiac surgery. However, its role in TAVR remains controversial due to significant variability in clinical practice. While some centers advocate routine protamine administration to enhance hemostasis and reduce bleeding, others selectively use it based on bleeding risk, citing concerns over adverse effects such as hypotension, allergic reactions, and thrombotic complications.
Recent studies have sought to define the optimal approach to heparin reversal during TAVR. Observational data suggest that full-dose protamine administration may reduce major bleeding events without increasing thrombotic risks, yet findings from randomized controlled trials remain inconsistent, particularly regarding mortality and vascular outcomes. , Furthermore, the comparative efficacy of full-dose versus partial or no protamine reversal remains insufficiently explored, resulting in a lack of consensus to inform clinical guidelines.
To address these uncertainties, we conducted a systematic review and meta-analysis to evaluate the safety and efficacy of protamine administration during transfemoral TAVR. By integrating data from randomized controlled trials and observational cohort studies, this analysis aims to clarify the impact of full-dose protamine on key clinical outcomes, guide decision-making in current practice, and optimize anticoagulation management strategies for TAVR procedures.
Methods
This systematic review and meta-analysis were performed and reported following the Cochrane Collaboration Handbook for Systematic Review of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement guidelines. ,
The study protocol was registered with PROSPERO, the International Prospective Register of Systematic Reviews (CRD420251134743) after completion of study selection and data extraction, to ensure public availability of the methodology.
Data source and search strategy
We systematically searched PubMed, Embase, and Cochrane databases. The search was last updated on April 10, 2025. The search terms included “TAVI,” “TAVR,” “protamine,” “heparin reversal,” and “low-dose protamine” The complete search strategy is provided in the online supplement. All records retrieved were independently assessed by two authors (B.V.N. and O.B.), and decisions regarding full-text retrieval were made by consensus. Full texts were reviewed by B.V.N. and O.B. and discussed regarding inclusion and exclusion criteria.
Eligibility criteria
We included randomized controlled trials (RCTs) and observational cohort studies comparing full heparin antagonization with protamine to partial or no antagonization during transfemoral transcatheter aortic valve implantation (TAVI). Studies were required to report at least one of the predefined clinical outcomes.
Exclusion criteria included studies without a control group, those focusing exclusively on surgical aortic valve replacement (SAVR), studies involving pediatric populations, overlapping study populations, or nonpeer-reviewed articles, such as conference abstracts. Studies with incomplete or missing datasets were also excluded.
Endpoints and sensitivity analyses
The outcomes of interest were selected based on clinical relevance and consistency with the Valve Academic Research Consortium-3 (VARC-3) definitions. These included: 1) a composite of all-cause mortality, major bleeding, and major vascular complications; 2) major vascular complications; 3) major bleeding; 4) all-cause mortality; and 5) stroke. Leave-one-out sensitivity analyses were performed for all endpoints.
Assessment of risk of bias
The risk of bias in RCTs was assessed using version 2 of the Cochrane Risk of Bias tool (RoB 2). nonrandomized studies were evaluated using the Risk of Bias in nonrandomized Studies– of Interventions (ROBINS-I) tool. , Two independent authors (J.P.M.R.J.S. and O.B.) assessed the risk of bias, resolving disagreements through discussion.
Statistical analyses
Effect measures were reported as risk ratios (RR) with 95% confidence intervals (CIs) for categorical outcomes. Meta-analysis was conducted using fixed- or random-effects models based on statistical heterogeneity, assessed via Cochran’s Q test and I² statistics (significance defined as p < 0.10 and I² > 25%). Publication bias was assessed with the Egger regression test and funnel plots for all endpoints. , Statistical analyses were performed using R software (version 4.3.3, R Project for Statistical Computing) within RStudio (R Foundation for Statistical Computing, Vienna, Austria), using the extension packages meta, metafor, and dmetar.
Results
Study selection and baseline characteristics
The initial search yielded 185 records. After removing duplicates and ineligible studies, 10 were fully assessed for eligibility, and 5 studies were included, comprising 2 randomized controlled trials and 3 observational cohort studies, totaling 3,089 patients. The PRISMA flow diagram is presented in Figure 1 , and Table 1 summarizes the key characteristics of the included studies. For studies using propensity score matching (PSM), baseline data were extracted from the matched cohorts, as these populations formed the basis of the outcome analyses.
PRISMA flow diagram. Flowchart of study selection showing the number of records identified, screened, excluded, and included in the systematic review and meta-analysis.
Table 1
Studies characteristics
| Author | Year of publication | No. of patients | Study design | Dose of protamine | Control | Reported Endpoints |
|---|---|---|---|---|---|---|
| Al-Kassou | 2020 | 873 | Prospective,single-center, non-randomized |
1.0 mg of protamine for every 100 units
of heparin |
No protamine | Major bleeding, mortality, stroke |
| Al-Kassou | 2022 | 1446 |
Prospective,
multicenter, non-randomized |
0.9 to 1.0 mg of
protamine for every 100 units of heparin |
0.4 to 0.6 mg of
protamine for every 100 units of heparin |
Major bleeding, mortality,
stroke |
| Kneizeh et al. | 2023 | 260 |
Retrospective,
single-center, non- randomized |
1.0 mg of protamine
for every 100 units of heparin |
0.5 mg of protamine
for every 100 units of UFH |
Stroke |
|
Vriesendorp
et al. |
2024 | 410 |
Randomized,
double-blinded, multicenter |
1.0 mg of protamine
for every 100 units of heparin |
Placebo |
Major bleeding, mortality,
stroke |
| Zbroński et al. | 2021 | 100 |
Randomized,
single-blinded, single-center |
1.0 mg of protamine
for every 100 units of heparin |
Placebo |
Major bleeding, mortality,
stroke |
*Mean.
Table 2 presents the baseline characteristics of patients stratified by treatment group: standard-dose protamine (SDP) versus low-dose or no protamine (PLD/NP). The mean or median age in the SDP group ranged from 79.7 to 82.0 years, and from 75.0 to 85.6 years in the PLD/NP group. The proportion of female patients ranged from 34.2% to 61.5% in the SDP group, and 40.0% to 55.2% in the PLD/NP group. Diabetes mellitus was reported in 26.7–51.0% of SDP patients and 29.6–43.8% of PLD/NP patients. Hypertension prevalence ranged from 77.7 to 88.3% in SDP and 76.0–88.9% in PLD/NP. History of prior stroke ranged from 8.5% to 20.5% in SDP and 5.7% to 15.6% in PLD/NP. Coronary artery disease (CAD) was reported in 16.4% to 79.0% of SDP patients and 62.6% to 97.7% of PLD/NP patients, though the lower limit in SDP may reflect an outlier. Hemoglobin levels ranged from 9.8 to 12.8 g/dL in SDP and 8.8 to 13.7 g/dL in PLD/NP. Left ventricular ejection fraction (LVEF) was reported between 55.9% and 60.0% in SDP and 50.1% to 58.0% in PLD/NP. Oral anticoagulant (OAC) use ranged from 10.6% to 47.0% in SDP, compared to 5.7% to 45.0% in PLD/NP.
Table 2
Baseline patients’ characteristics
| Study |
Age, y
(mean ± SD) |
Female
(%) |
Diabetes
(%) |
Hypertension
(%) |
Prior stroke
(%) |
CAD
(%) |
Hemoglobin, g/dL
(mean±SD) |
LVEF %
(mean ± SD) |
OAC
(%) |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SDP | LDP/NP | SDP | LDP/NP | SDP | PLD/NP | SDP | LDP/NP | PSD | LDP/NP | SDP | LDP/NP | SDP | LDP/NP | SDP | LDP/NP | SDP | LDP/NP | |
|
Al-Kassou
et al. |
81.3 ± 5.9 | 80.0 ± 6.4 | 50.5 | 50.0 | 26.7 | 29.6 | NA | 9.7 | 9.2 | 59.2 | 68.4 | 11.6 ± 1.9 | 11.5 ± 1.8 | 56.5 ± 11.2 | 55.9 ± 12.6 | 15.4 | 9.2 | |
|
Al-Kassou
et al. |
81.3 ± 5.8 | 80.8 ± 6.2 | 49.2 | 55.2 | 27.9 | 31.3 | 88.3 | 88.9 | 12.0 | 11.2 | 61.5 | 66.0 | 11.7 ± 1.8 | 12.3 ± 1.6 | 55.9 ± 11.6 | 55.3 ± 12.0 | 42.6 | 42.9 |
| Kneizeh et al. * | 80 (77–84)‡ | 82 (78–85)‡ | 40.0 | 40.0 | 43.8 | 33.8 | 77.7 | 76.0 | 13.8 | 13.8 | 76.2 | 97.7 |
12.3
(11.2–13.7)‡ |
11.9
(10.3-13.3)‡ |
NA | 40.0 | 32.3 | |
|
Vriesendorp
et al. |
82 (77-85)‡ | 80 (75-85)‡ | 34.2 | 42.2 | 33.2 | 22.7 | 78.4 | 81.9 | 8.5 | 5.7 | 69.8 | 72.0 |
12.8
(11.6-13.8)‡ |
12.9
(11.6-13.8)‡ |
60 (55-65)‡ | 60 (55-64)‡ | 10.6 | 5.7 |
| Zbroński et al. | 81.8 (77–85)‡ | 81 (75–86)‡ | 53.0 | 51.0 | 51.0 | 36.0 | 87.0 | 87.0 | 9.0 | 15.0 | 79.0 | 72.0 |
9.8
(8.8–11.1)‡ |
9.8
(8.8–10.8)‡ |
60 (55–64)‡ | 58 (53–62)‡ | 47.0 | 45.0 |
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