Clinical Trial of 3 Nasal Sprays For HHT Nosebleeds Showed None Better Than Placebo Interview with:

Dr. Kevin J. Whitehead MD Adjunct Associate Professor, Pediatrics Associate Professor, Internal Medicine University of Utah

Dr. Kevin Whitehead

Dr. Kevin J. Whitehead MD
Adjunct Associate Professor, Pediatrics
Associate Professor, Internal Medicine
University of Utah What is the background for this study?

Response: Hereditary hemorrhagic telangiectasia (or Osler-Weber-Rendu Syndrome) is a genetic vascular malformation syndrome that results in arteriovenous malformations. This syndrome is found in 1:5000 individuals, and is inherited in autosomal dominant fashion. It is often under diagnosed by the medical community (some estimate that 90% of patients do not know that they are affected).

In the skin and mucous membranes small AVMs – termed telangiectasias – form, and they have the potential to rupture and bleed. This happens most commonly in the nose, and 95% of patients with HHT have recurrent nose bleeding (epistaxis). While other dangerous internal organ AVMs also form, epistaxis is the most important determinant of quality of life for these patients. This epistaxis can lead to anemia, heart failure and rarely death. Patients often seek therapy for epistaxis, but cautery or laser treatment of the telangiectasias tends to provide only temporary benefit. Definitive therapy to eliminate epistaxis requires surgical closure of the nasal passages, and is too drastic for most patients.

We sought to test medical therapy for HHT-related epistaxis with our best candidate drugs in nose spray form. The drugs with the most anecdotal support include bevacizumab (an anti-angiogenic drug), estriol (an estrogen), and tranexamic acid (an inhibitor of fibrinolysis). Our patients received a nose spray with one of these drugs or a saline placebo and used two sprays in each nostril daily for 12 weeks and recorded their nose bleed frequency and duration in a daily diary. What are the main findings?

Response: We found that no medication was any better than the saline placebo at decreasing epistaxis frequency. The median nosebleed frequency was very close to 7 for all four treatment arms (equivalent of one nose bleed per day). Specifically we found that the median epistaxis frequency (with interquartile range) was 8.0 (3.0-14.0) for placebo, 7.0 (4.5-10.5) for bevacizumab, 8.0 (4.0-12.0) for estriol, and 7.5 (3.0-11.0) for tranexamic acid – a non-significant difference. The Epistaxis Severity Score (a validated index of HHT related epistaxis severity) did show a meaningful improvement for all four groups, including placebo, with no greater improvement for any drug therapy. What should readers take away from your report?

Response: Topical treatment of HHT-related epistaxis with either bevacizumab, estriol or tranexamic acid offers no greater advantage than placebo. The use of saline hydration on a routine basis for patients with frequent HHT-related epistaxis is a simple, low-risk intervention that may actually help decrease epistaxis severity (a placebo effect cannot be excluded). What recommendations do you have for future research as a result of this study?

Response: Future trials of medical therapy for HHT-related epistaxis are needed, and there is the possibility that the doses chosen for this study (especially for bevacizumab) may have been too low, or that using a mucoadhesive polymer to increase the exposure time to the mucosa would improve efficacy. We would also strongly encourage the use of a run-in period of observation on placebo therapy to establish the baseline epistaxis severity against which the effect of therapy would be compared. Is there anything else you would like to add?

Response: First, we would like to increase patient and physician awareness of HHT as a cause for recurrent epistaxis. HHT should be suspected in patients with recurrent epistaxis and a family history of epistaxis (even if mild). Such patients should be evaluated at any one of a growing network of HHT Centers of Excellence (information can be found at

Second, we would like to highlight our success in funding, recruiting and executing an adequately powered randomized clinical trial for a rare disease. Clinical trials are possible, even for rare diseases. This study was funded by the patient organization, Cure HHT. The costs of the study were all covered by donations and fundraising through this collection of motivated patients and family members. Although our sites tend to act as regional referral centers, no single center has enough patients meeting criteria to have an adequately powered study over a reasonable period of time, and the coordination achieved through the Cure HHT Clinical Centers of Excellence and the good communication that exists among these centers was necessary to achieve this. Thank you for your contribution to the community.


Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on September 8, 2016 by Marie Benz MD FAAD