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Original Investigation |

Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia A Randomized Clinical Trial

Kevin J. Whitehead, MD1,2; Nathan B. Sautter, MD3; Justin P. McWilliams, MD4; Murali M. Chakinala, MD5; Christian A. Merlo, MD, MPH6; Maribeth H. Johnson, MS7; Melissa James, BSN, RN8; Eric M. Everett, RPh9; Marianne S. Clancy, MPA10; Marie E. Faughnan, MD11,12; S. Paul Oh, PhD13; Scott E. Olitsky, MD14; Reed E. Pyeritz, MD, PhD15; James R. Gossage, MD8
[+] Author Affiliations
1Division of Cardiovascular Medicine and Pediatric Cardiology, Utah HHT Center of Excellence, University of Utah, Salt Lake City
2George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah
3Oregon Sinus Center, Department of Otolaryngology–Head and Neck Surgery, Oregon Health & Science University, Portland
4Division of Interventional Radiology, Department of Radiology, UCLA HHT Center of Excellence, David Geffen School of Medicine at UCLA, Los Angeles, California
5Division of Pulmonary and Critical Care, Washington University School of Medicine, St Louis, Missouri
6Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland
7Department of Biostatistics and Epidemiology, Augusta University, Augusta, Georgia
8Division of Pulmonary and Critical Care Medicine, Augusta University, Augusta, Georgia
9O’Brien Pharmacy, Mission, Kansas
10Cure HHT, Monkton, Maryland
11Toronto HHT Program, Division of Respirology, Department of Medicine, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
12Keenan Research Centre and Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Ontario, Canada
13Department of Physiology and Functional Genomics, University of Florida, Gainesville
14Department of Ophthalmology, Children’s Mercy Hospital, Kansas City, Missouri
15Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
JAMA. 2016;316(9):943-951. doi:10.1001/jama.2016.11724.
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Importance  Epistaxis is a major factor negatively affecting quality of life in patients with hereditary hemorrhagic telangiectasia (HHT; also known as Osler-Weber-Rendu disease). Optimal treatment for HHT-related epistaxis is uncertain.

Objective  To determine whether topical therapy with any of 3 drugs with differing mechanisms of action is effective in reducing HHT-related epistaxis.

Design, Setting, and Participants  The North American Study of Epistaxis in HHT was a double-blind, placebo-controlled randomized clinical trial performed at 6 HHT centers of excellence. From August 2011 through March 2014, there were 121 adult patients who met the clinical criteria for HHT and had experienced HHT-related epistaxis with an Epistaxis Severity Score of at least 3.0. Follow-up was completed in September 2014.

Interventions  Patients received twice-daily nose sprays for 12 weeks with either bevacizumab 1% (4 mg/d), estriol 0.1% (0.4 mg/d), tranexamic acid 10% (40 mg/d), or placebo (0.9% saline).

Main Outcomes and Measures  The primary outcome was median weekly epistaxis frequency during weeks 5 through 12. Secondary outcomes included median duration of epistaxis during weeks 5 through 12, Epistaxis Severity Score, level of hemoglobin, level of ferritin, need for transfusion, emergency department visits, and treatment failure.

Results  Among the 121 patients who were randomized (mean age, 52.8 years [SD, 12.9 years]; 44% women with a median of 7.0 weekly episodes of epistaxis [interquartile range {IQR}, 3.0-14.0]), 106 patients completed the study duration for the primary outcome measure (43 were women [41%]). Drug therapy did not significantly reduce epistaxis frequency (P = .97). After 12 weeks of treatment, the median weekly number of bleeding episodes was 7.0 (IQR, 4.5-10.5) for patients in the bevacizumab group, 8.0 (IQR, 4.0-12.0) for the estriol group, 7.5 (IQR, 3.0-11.0) for the tranexamic acid group, and 8.0 (IQR, 3.0-14.0) for the placebo group. No drug treatment was significantly different from placebo for epistaxis duration. All groups had a significant improvement in Epistaxis Severity Score at weeks 12 and 24. There were no significant differences between groups for hemoglobin level, ferritin level, treatment failure, need for transfusion, or emergency department visits.

Conclusions and Relevance  Among patients with HHT, there were no significant between-group differences in the use of topical intranasal treatment with bevacizumab vs estriol vs tranexamic acid vs placebo and epistaxis frequency.

Trial Registration  clinicaltrials.gov Identifier: NCT01408030

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Figure 1.
Flow Diagram of Patients in the North American Study of Epistaxis in HHT

Patients were screened for eligibility at the 6 participating hereditary hemorrhagic telangiectasia (HHT) centers of excellence. The number assessed for eligibility is an estimate based on the number of patients with HHT-related epistaxis (HRE) seen annually at each site and the number of months each site was enrolling patients. The specific reasons for exclusion were not prospectively recorded. The number of exclusions is an estimate based on data from the Augusta University center of excellence showing that 89% of patients with HRE have 1 or more epistaxis episodes per week.

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Figure 2.
Change in Epistaxis Severity Score With Topical Endonasal Therapy in the North American Study of Epistaxis in HHT

Data markers indicate least-squares means and 95% CIs. Patients reported epistaxis severity using the Epistaxis Severity Score (ESS), which is a validated tool to quantify hereditary hemorrhagic telangiectasia–related epistaxis on the basis of responses to 6 weighted questions. The scores range from 0 to 10 with higher scores reflecting greater epistaxis severity. The overall mean ESS at baseline for the combined groups is shown for reference, together with the established threshold for the minimally important difference (0.71).18 No treatment group differences were significant. Groups were compared using a mixed-model repeated-measures analysis of variance to analyze ESS for treatment and time effects. Each treatment group experienced a significant improvement from baseline (week 0) to the end of the active treatment phase at week 12 (P < .001). Compared with week 12, all groups had worsened by the end of the observation phase at week 24 (P = .01), but this remained an improvement compared with baseline (P < .001). The degree of improvement compared with baseline remained greater than the established minimally important difference for all groups by the end of week 24.

aAfter randomization, 1 patient was excluded for the protocol violation of using an estrogen-containing medication, leaving 30 patients in this group.

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