A Systematic Review On The Use Of Pharmacological Agents In Patients With Hereditary Hemorrhagic Telangiectasia (HHT)
Authors: Radwi Mansoor , Ponnampalam Arjuna , Faughnan Marie E , Shehata Nadine 
Published: October 2019

Introduction
Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder that affects approximately 1 in 5,000 people. Recurrent epistaxis occurs in 90% of adults & chronic GI bleeding in 20%, and when severe may require transfusion support, repeat emergency department visits & admissions for endoscopic/surgical intervention. Use of various systemic & topical agents to reduce bleeding & its associated co-morbidities are highly needed.
We conducted a systematic review to determine if the use of pharmacological agents in patients with HHT reduces bleeding, mortality due to bleeding, frequency of transfusion, frequency of hospital admissions/visits, or improved quality of life.

Methods
We searched MEDLINE & EMBASE from 1946 to February 2013 for medical treatments used to control bleeding (e.g. antifibrinolytics agent, angiogenic inhibitors, estrogen) in patients with HHT. We excluded articles if they were animal studies, case reports, letters, reviews, series with < 5 patients, or not published in English language. We also included conference proceedings published in the last 5 years (2008-2013).

Results
2 independent reviewers assessed 414 citations. Of these, 21 nonrandomized trials (15 prospective & 6 retrospective) & 4 randomized controlled trials (RCT) met our criteria for inclusion. From 25 trials reviewed, 21 had sample sizes fewer than 50 participants. The spectrum of medical therapy studied included estrogens, antiestrogens, antifibrinolytics & angiogenesis inhibitors: Bevacizumab was the most evaluated agent (10 trials) followed by hormonal therapy (9 trials).
Measured outcomes included the Epistaxis Severity Score (ESS), change in hemoglobin concentration (Hb), the Sadick scale score (a scale evaluating amount & frequency of epistaxis), intensity & frequency of bleeding, hemorrhage free time, & quality of life (QoL). The metrics used to evaluate outcomes were heterogeneous across the studies & therefore a meta-analysis was not performed on available data.
When using Bevacizumab, ESS scores (reported in 5 of 10 trials) significantly improved in 4 trials (mean ranges pre intervention: 6-8.12 vs. post intervention: 2.82-3.6) while Hb levels (reported in 4 of 10 trials) showed significant improvement in 3 trials (mean ranges pre-intervention: 85-106 g/L vs. post intervention: 97-130 g/L). QoL (reported in 4 of 10 trials), was reported to be improved in 3 trials.
Hormonal therapy was also effective. Topical hormonal therapy combined with Argon plasma coagulation (APC) showed significant efficacy in 2 trials. Decreased intensity of bleeding (67-71% of patients converted from grade 3 to grade 1) & frequency of bleeding (68-69% of patients converted from grade 3 to grade 1) were reported. Oral estrogen & tranexamic acid trials yielded mixed results. On the other hand, a prospective trial using raloxifine showed improvement in Sadick scale score (Mean Frequency: pre 2.36, post 1.13, Mean Quantity: pre 2.26, post 1.42), & a rise in hemoglobin of 9.25 % (before treatment 11.18 ± 0.10, after treatment 12.08 ± 0.15). Tamoxifen therapy showed a significant improvement in severity & frequency of epistaxis in a RCT & an additional observational trial showed improvement in epistaxis bleeding score, hemoglobin & quality of life.
Side effects (SE) were reported in 13 trials. Topical Bevacizumab alone had no side effects (3 out 4 trials reported SE), however when combined with laser treatment in high doses, 40% of patients developed septal perforation in one trial. Side effects were seen in 84% of patients receiving IV Bevacizumab, most common SE were headache (58% of events), nausea & vomiting (13% of events). 3 trials that used oral estrogen reported vaginal bleeding (10-50%) & gynecomastia/breast engorgement (33-47%). No thromboembolic events were reported. Topical hormonal treatment did not result in side effects although only one trial reported events.

Conclusion
Bevacizumab, tamoxifen & combined topical hormonal with Argon plasma coagulation therapy appear to be effective in reducing bleeding for patients with HHT. Other agents such raloxifine & thalidomide also showed improvement in outcomes but further studies are needed to evaluate their efficacy. Limitations include a lack of a well-structured RCT, the predominance of small non-randomized trials, & a lack of coherent data reporting on outcomes.

Disclosures:
No relevant conflicts of interest to declare.