Efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. A double-blind, randomized, placebo-controlled trial

Abstract

Hereditary hemorrhagic telangiectasia is a rare vascular genetic disease. Epistaxis is the most frequent and disabling manifestation, and timolol appears to be a new therapeutic option as non-selective beta-blockers have in vitro and in vivo anti-angiogenic properties. Our main objective was to evaluate the efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. This study is a single-center, randomized, phase 2, double-blind placebo-controlled study with an allocation ratio of 1:1. It was proposed to patients with hereditary hemorrhagic telangiectasia monitored at the French Reference Center, and we included patients aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis. The treatment was self-administered by the patient with a posology of one spray (50 µL) of timolol 0.5% or placebo in each nostril twice a day for 28 consecutive days. The primary efficacy endpoint was mean monthly epistaxis duration, assessed by monitoring epistaxis grids. A total of 58 patients were randomized and treated. The baseline characteristics were similar in the 2 groups. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 26 patients receiving the drug in comparison with the placebo group (p = 0.54). Toxicity was low and no severe adverse events were reported. One limitation is that we included all HHT patients with nosebleeds and did not take into account history of nasal surgery or nasal crusts. Timolol, administered by nasal spray at a dose of 0.25 mg in each nostril twice a day for 28 consecutive days, did not improve epistaxis in patients with hereditary hemorrhagic telangiectasia at 4 months after the beginning of the treatment.

An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study

“… 32 Topical nasal pharmacotherapy has been similarly disappointing, with randomized studies of topical timolol, estrogen, and tranexamic acid all showing no difference in the comparison with placebo. 33 , 34 Bevacizumab via topical nasal spray has also been evaluated, with no improvement noted in epistaxis severity in the comparison with placebo. 33 , 35 Therefore, given the lack of other effective options and the continued lack of any Food and Drug Administration-approved treatment, our findings suggest it may be appropriate to consider systemic bevacizumab in patients with moderate-to-severe HHT-associated bleeding ( Online Supplementary Table S1 ) without contraindications.…”

Improvement in epistaxis management: the experience of a dedicated hereditary haemorrhagic telangiectasia clinic

“…The studies cited have also noted no adverse effects following the initiation of beta blockers when contraindications are considered. 8,9,13 The observed improvement of ESS for these patients is likely multifactorial. Whilst it is possible that topical +/À systemic beta blocker could improve symptoms, the prolonged and accessible support from the multidisciplinary team and simple regimented application of nasal emollients could also contribute to the improvement of ESS.…”

Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions

“…Thus, blood pressure lowering medication may be beneficial. Propranolol, a nonselective β-blocker with antiangiogenic effects, has shown some benefit used topically on nasal telangiectases [73], although a double blind randomized placebo-controlled trial using topical application of the β-blocker Timolol showed no benefit on epistaxis [53].…”