Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study

Abstract

The inhibiting effects of itraconazole, an antifungal drug on vascular endothelial growth factor (VEGF) have recently been discovered. By inhibiting VEGF, itraconazole has shown potential in clinical trials as anti-cancer treatment. In hereditary hemorrhagic telangiectasia (HHT) patients, VEGF levels are elevated and inhibition of VEGF can decrease bleeding. Itraconazole could potentially serve as anti-angiogenic therapy for HHT-related bleeding. We report a proof of concept study with HHT patients and severe epistaxis. Patients were treated with daily 200 mg orally administered itraconazole for sixteen weeks. Twenty-one HHT patients, 8 females (38%), 13 males (62%), median age of 59 years (interquartile range (IQR) 55–69) were enrolled. Of these patients, 13 (62%) were diagnosed with HHT type 1, seven (33%) with HHT type 2 and in one patient (5%), no pathognomonic HHT mutation was found. Four patients (19%) prematurely terminated the study (3 due to mild or moderate side-effects) resulting in 17 patients included in the analyses. The median epistaxis severity score significantly decreased during treatment from 6.0 (IQR 5.1–7.2) to 3.8 (IQR 3.1–5.2) (p = 0.006). The monthly epistaxis frequency decreased from 56 to 38 epistaxis episodes (p = 0.004) and the monthly duration from 407 to 278 minutes (p = 0.005). Hemoglobin levels did not significantly change. The quality of life showed a small but significant improvement. In conclusion, oral itraconazole significantly improved epistaxis in HHT patients. The potential benefit of itraconazole in HHT should be further investigated.

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Abbreviations

ACVRL1:

Activin A receptor like type 1

AE:

Adverse event

APC:

Argon plasma coagulation

ENG:

Endoglin

ESS:

Epistaxis severity score

HHT:

Hereditary hemorrhagic telangiectasia

IQR:

Interquartile range

MCS:

Mental component summary

MFI-20:

Multidimensional fatigue inventory 20

PCS:

Physical component summary

RBC:

Red blood cell

SAE:

Severe adverse event

SF-36:

Short Form Health Survey 36

VEGF:

Vascular endothelial growth factor

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Contributions

Study concept and design: SK; RJS; FJMD; MCP, JJM. Acquisition of the data: SK; RJS; MCP, JJM. Analysis and Interpretation of data: SK; RJS; AEH; VVMV; FJMD; MC Post, JJM. Critical writing of the manuscript: SK. Revising the intellectual content: SK; RJS; AEH; VVMV; FJMD; MCP, JJM. Final approval of the version to be published: SK; RJS; AEH; VVMV; FJMD; MCP, JJM.

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Correspondence to J. J. Mager.

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Kroon, S., Snijder, R.J., Hosman, A.E. et al. Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study. Angiogenesis (2020). https://doi.org/10.1007/s10456-020-09758-2

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Keywords

  • Anemia
  • Epistaxis
  • Telangiectasia, Hereditary hemorrhagic
  • Vascular endothelial growth factors