# Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

- **DOI:** [10.1016/s0140-6736(23)00350-1](https://doi.org/10.1016/s0140-6736(23)00350-1)
- **Rating:** Strong (4.1 out of 5)
- **Verdict:** Garadacimab delivers a large six-month reduction in hereditary angioedema attacks, but the small, demographically narrow cohort limits broader safety and transferability.
- **Framework version:** v5.9
- **Pipeline version:** v0.4
- **Evaluation date:** 2026-09-18
- **Evaluation page:** https://www.nabu.science/paper/10.1016%2Fs0140-6736(23)00350-1

## Key claims

1. the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group than in the placebo group
   - Support: Well-supported
   - Type: Primary finding
   - Basis: direct randomised comparison with a large effect and consistent baseline-adjusted sensitivity analysis
   - Location: Findings, Abstract; Table 2
2. the majority (62%) were attack-free during the entire 6 months of treatment compared with no patients who received placebo
   - Support: Supported
   - Type: Secondary
   - Basis: large observed difference, tempered by the small cohort and excluded short-exposure placebo participant
   - Location: Research in Context, p.1080; Table 2
3. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events
   - Support: Tentative
   - Type: Secondary
   - Basis: no events occurred, but 39 exposed participants over six months cannot resolve rare-event risk
   - Location: Findings, Abstract; Table 3; Discussion, p.1088

## Strengths

- **Large prespecified effect on attack rates** The primary analysis found 0.27 investigator-confirmed attacks per month with garadacimab versus 2.01 with placebo, an 87% difference in means with p<0.0001. A baseline-adjusted count-model sensitivity analysis produced a similar 89% difference.
  - Dimension: contribution
  - Location: Results and Table 2, pp.1083–85
- **Strong randomisation and masking procedures** Allocation was centrally managed through IRT, stratified by age and baseline attack rate, and concealed from sites and relevant funder representatives. Indistinguishable, volume-matched syringes supported masking.
  - Dimension: methodological rigour
  - Location: Randomisation and Masking, p.1082
- **Clear route toward clinical use** The study tested monthly self- or caregiver-administered prophylaxis in a pivotal phase 3 trial conducted under a US Biological License Application. The intervention targets a defined specialist-managed population with guideline-recognised treatment goals.
  - Dimension: application pathway
  - Location: Study Design and Participants, p.1081; Procedures, p.1082; Discussion, p.1088

## Limitations

- **Analysis population is not fully consistent** The Methods defines efficacy analysis as intention-to-treat, but Table 2 and Figure 2 exclude one placebo participant with fewer than 30 treatment days. Three additional placebo participants discontinued because of attacks, and no attrition-specific sensitivity analysis is reported.
  - Dimension: methodological rigour
  - Location: Statistical Analysis, p.1084; Table 2; Figure 1; Results, p.1085
- **Sponsor analysis roles remain intertwined** The funder contributed to design, collection, analysis, interpretation, writing, and submission, while sponsor-employed authors participated in formal analysis and data verification. The relationship between those roles and the stated independent third-party analysis is not fully explained.
  - Dimension: methodological rigour
  - Location: Methods, p.1081; Role of the Funding Source, p.1085; Contributors, p.1088
- **Population breadth and duration are limited** The safety population comprised 64 participants followed for six months, including only six adolescents, and 86% were White. These features constrain inference about rare harms and transferability across age and ancestry groups.
  - Dimension: application pathway
  - Location: Table 1, p.1082; Results, p.1085; Discussion, p.1088

## Reliability checks

Caveats (4 of 4 checks).

- **Internal coherence:** Noted. The principal results reconcile across the abstract, figures, and tables, but the stated intention-to-treat definition is not fully consistent with the exclusion of one placebo participant from efficacy analyses. The relationship between independent third-party analysis and sponsor participation in analysis is also not fully explained.
- **Research conduct:** Noted. Ethics approval, consent, prospective registration, conflicts of interest, and a data-request process are disclosed. Sponsor involvement extended from study design through analysis, interpretation, writing, and submission, making analytical independence a disclosed conduct consideration.
- **Reference integrity:** Clean. 19 of 19 checkable references verified
  - 20 references in manuscript
  - 1 have no canonical index record — counted, but not index-checkable
  - 1 reference confirmed by manual review
  - References not verified automatically are resolved manually within 24 hours.

## Post-publication record

- **Status:** Clean
- **Summary:** No retraction or expression of concern found in Crossref (includes Retraction Watch).
- **Erratum published 15 Apr 2023**, listed in Crossref: https://doi.org/10.1016/s0140-6736(23)00739-0
- **Last checked:** 2026-10-17