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Data about the efficacy and safety of routine protamine sulphate to prevent these complications remain scarce. Hence, we aim to assess the efficacy and safety of routine protamine sulphate use for heparin reversal in patients undergoing percutaneous cardiac interventions. We systematically searched PubMed, Embase, Cochrane, Scopus, and Web of Science for randomized controlled trials (RCTs) until September 2024. The RCTs\u2019 quality was assessed using the Cochrane tool (RoB 2). Using R, we pooled dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD), both along the corresponding 95% Confidence interval (CI). PROSPERO ID: (CRD42024593002). Six RCTs with 1,076 patients were eligible. Hemostasis success was significantly higher in the protamine group (RR, 1.06; 95% CI [1.01\u20131.10];\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.01), and the length of hospital stay was significantly shorter (MD, -0.46; 95% CI [-0.65, -0.26];\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.01). There was no significant difference between both groups in stroke (RR, 0.60; 95% CI [0.18\u20132.03];\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.41), major bleeding (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.25), minor bleeding (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.11), life-threatening bleeding (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.65), time to ambulation (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.13), all-cause mortality (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.92), hematoma\/pseudoaneurysm (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.92), and major vascular complications (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.70). While protamine improved hemostasis success, its effect on reducing bleeding events and time to ambulation was insignificant. Also, reducing the length of hospital stay in the protamine group highlights its potential clinical benefit.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04369-4","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T04:38:06Z","timestamp":1751603886000},"page":"16507-16520","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Protamine sulphate for heparin reversal in percutaneous cardiac interventions: a systematic review and meta-analysis of randomized controlled trials"],"prefix":"10.1007","volume":"398","author":[{"given":"Elsayed","family":"Balbaa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed Farid","family":"Gadelmawla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdelrahman M.","family":"Tawfik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed","family":"Naeem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed","family":"Elbataa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad","family":"Bazzazeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed Ramadan","family":"Fatiem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khaled","family":"Ali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Obieda","family":"Altobaishat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Abuelazm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"4369_CR1","doi-asserted-by":"publisher","unstructured":"Abdelazeem B, Abuelazm MT, Swed S, Gamal M, Atef M, Al-Zeftawy MA et al (2022) The efficacy of nitroglycerin to prevent radial artery spasm and occlusion during and after transradial catheterization: A systematic review and meta-analysis of randomized controlled trials. 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