Medical Treatments of Epistaxis in Hereditary Hemorrhagic Telangiectasia: An Updated Systemic Review and Meta-Analysis of Randomized Control Trials
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Background: Epistaxis is the most frequent and clinically burdensome manifestation of hereditary hemorrhagic telangiectasia (HHT), yet pharmacological trials vary considerably in intervention class, route of administration, study design, and outcome definition. Objective: To evaluate the efficacy and safety of pharmacological treatments for HHT-related epistaxis and to integrate pooled treatment effects with complementary randomized evidence across the evolving therapeutic landscape. Methods: This systematic review was registered in PROSPERO (CRD420251013449) and reported in accordance with PRISMA 2020. PubMed, Scopus, and Web of Science were searched from inception to February 2025. Meta-analysis was performed in RevMan 5.4.1 using random-effects models, mean differences (MDs) for continuous outcomes, risk ratios (RRs) for binary outcomes, and I² to quantify heterogeneity. Risk of bias was assessed using the Cochrane RoB 1 tool, and certainty of evidence was evaluated using GRADE. Quantitative estimates were derived from the predefined meta-analytic dataset, while additional eligible randomized trials were synthesized narratively when they were not incorporated into the pooled analyses. Results: The quantitative synthesis comprised 12 comparative studies, including one retrospective comparative study. Bevacizumab did not significantly reduce epistaxis frequency (MD −0.30, 95% CI −5.17 to 4.58) or duration (MD −26.87 min/month, 95% CI −112.32 to 58.58), and no significant improvement was observed in hemoglobin concentration (MD 0.37, 95% CI −0.86 to 1.60) or overall adverse-event risk (RR 1.00, 95% CI 0.85 to 1.19). A small but statistically significant reduction in Epistaxis Severity Score (ESS) favored bevacizumab (MD −0.22, 95% CI −0.38 to −0.05; I²=14%). Tranexamic acid showed no significant pooled effects on epistaxis frequency, duration, or hemoglobin concentration, with considerable heterogeneity in the primary analyses (I²=92%–94%). Timolol showed no significant pooled differences in adverse events or hemoglobin concentration, while estrogen/estriol did not significantly reduce epistaxis frequency. GRADE certainty ranged from moderate to very low across outcomes. Complementary randomized evidence expanded the therapeutic profile: topical propranolol produced a significant ESS benefit in a small randomized trial; pomalidomide reduced ESS by 0.94 points versus placebo at 24 weeks in PATH-HHT; and nintedanib did not meet its primary responder endpoint in EPICURE, although favorable secondary changes were observed in epistaxis duration and hemoglobin concentration. Conclusions: The pooled evidence demonstrates limited and inconsistent benefit for several established pharmacological interventions, with the clearest quantitative signal being a small reduction in ESS with bevacizumab. The broader randomized evidence indicates that clinically meaningful pharmacological benefit is achievable with selected therapies, particularly pomalidomide, while treatment effects vary according to drug mechanism, route of administration, disease severity, and outcome definition. Management of HHT-related epistaxis should therefore remain individualized, integrating bleeding burden, therapeutic mechanism, safety profile, route of administration, and certainty of evidence
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