Epistaxis is the most common symptom of HHT, developing in 90% of adults with the disease, affecting quality of life and often leading to iron deficiency and anemia. Typically, turbulent nasal airflow with breathing leads to mucosal dryness and bleeding from telangiectases of the nasal mucosa. As such, replacing lost moisture to help prevent the telangiectases from cracking and bleeding is a mainstay of epistaxis care. In a randomized clinical trial comparing topical therapies to saline as placebo, saline was found to significantly reduce the epistaxis severity score (ESS) at both 12 and 24 weeks after therapy(9).

In many patients, additional therapies are often considered, when symptoms are persistent or severe, despite moisturization. Tranexamic acid is an oral antifibrinolytic agent that can stabilize clots by preventing premature clot lysis and has been shown to decrease intraoperative bleeding in other conditions. Two RCTs (Supplement Table 2) of oral tranexamic acid demonstrated a significant decrease in epistaxis severity(10, 11) with minimal adverse events. Neither study showed a significant improvement in hemoglobin but baseline levels were normal or nearly normal in both studies so the opportunity for improvement may have been small. Three studies in HHT have not found an increased risk of thrombosis with tranexamic acid(10, 11, 44), though there remains concern that this agent should be avoided in patients at high risk for thrombosis (e.g. patients with a history of arterial thrombosis or unprovoked venous thrombosis), in patients with atrial fibrillation and patients with thrombophilia or elevated factor VIII.

Various ablative therapies have been studied in controlled and uncontrolled case series (Supplement Table 3). Lasers, including the Argon, potassium-titanyl-phosphate (KTP), and Nd-YAG lasers(15). Outcomes are variable, with at best temporary and partial improvement in epistaxis. However, side effects of laser treatments overall are relatively minor. Access can be limited by required laser safety precautions, local availability of specific lasers and costs. Sclerotherapy with foamed sodium tetradecyl sulfate to the nasal cavity can be performed in the outpatient setting under local anesthesia. Three studies using foamed sodium tetradecyl sulfate, including one RCT, all from the same investigators, concluded that sclerotherapy was effective and safe(12, 13, 108). The investigators found that bleeding was substantially better controlled after sclerotherapy than standard therapy with minimal adverse effects. Though rare, potential side effects include septal perforation, transient dizziness, blurred vision and permanent blindness(108). The literature regarding radiofrequency and electrosurgery treatment for nasal telangiectatic lesions is scarce; there are only a few studies showing efficacy of treatment. Bipolar electrosurgery, is preferred over monopolar electrosurgery, given its lower risk for collateral damage, specifically septal perforation. Radiofrequency cauterizes the telangiectasias at a lower temperature than electrocautery and reduces the risk for collateral damage(14). Overall, there is evidence that ablative therapies can provide temporary and partial improvement in epistaxis, and that side effects are mostly minor.

Severe epistaxis can be life threatening and devastating to QOL of HHT patients, and symptoms are often not adequately controlled with moisturization and ablative therapies. As such, systemic therapies and more invasive surgical management is often considered. Low level of evidence studies of antiangiogenic therapies are detailed in Supplement Table 3. Bevacizumab is a humanized recombinant monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) and has been shown to be effective in several diseases characterized by increased angiogenesis. From 2006 through 2019 there have been 3 prospective(16-18) and 5 retrospective studies(19-23) that evaluated the use of intravenous bevacizumab in HHT in 5 or more patients with HHT-related bleeding (152 total patients, most with epistaxis). Objective improvements were noted in the majority of studies that reported on epistaxis severity, hemoglobin level, RBC transfusion, and/or quality of life (QOL). The most commonly reported adverse events (AE) include hypertension(19) and arthralgia(73). Some studies have noted problems with wound healing, sometimes serious(17, 23). Overall, the evidence supports the effectiveness of IV bevacizumab in reducing epistaxis severity and RBC need, and improving anemia. However, in the absence of RCT, the magnitude of benefit and long-term safety are unclear. Of note, RCTs of topical (nasal) bevacizumab(9, 109) and intranasal bevacizumab injections(110), have not shown any significant benefit (Supplement Table 2).

Thalidomide and several of its analogs have been shown to downregulate VEGF levels in HHT patients(111) and improve blood vessel wall integrity(112). From 2007 through 2019 there have been 4 prospective(111-114) and 2 retrospective studies(115, 116) that evaluated the use of oral thalidomide in 5 or more patients with HHT-related epistaxis (67 total patients), detailed in Supplement Table 3. Objective improvements were noted in all but one study that reported on epistaxis severity, hemoglobin level, RBC transfusion, and/or QOL. Neuropathy is one of the most commonly reported side effects, often leading to discontinuation of the drug(73, 114, 115), and known teratogenicity precludes its use in women with child-bearing potential. Overall, low level evidence supports effectiveness of oral thalidomide in decreasing epistaxis severity and RBC need, and in improving anemia. However, AEs are substantial and often a limiting factor with neuropathy persisting even after discontinuation of the drug in two thirds of patients(73, 115).

Several other antiangiogenic agents are under investigation in the treatment of HHT related epistaxis. Pazopanib is a multikinase inhibitor that showed signs of efficacy in one small series(45). Pomalidomide is a thalidomide analog that appears to have a lesser incidence of neuropathy and is under study in a large RCT in HHT related bleeding. Doxycycline is an oral metalloproteinase inhibitor that may have downstream antiangiogenic effects and is under study in two small RCTs at present. The role of these agents in HHT related epistaxis will await additional studies.

Invasive surgical procedures are also often considered when epistaxis is not adequately controlled with moisturization and ablative therapies. Low level of evidence studies of invasive surgical procedures, including septodermoplasty and nasal closure, are detailed in Supplement Table 3. The expert panel considered invasive surgical procedures as an equal option to the systemic therapies, and that this decision requires extensive consultation with the patient. In addition, comorbid disease, such as atrial fibrillation, can limit the use of prothrombotic drugs and require even aggressive anticoagulation or antiplatelet therapy instead. In these cases the invasive surgical measures(24-29) may be more appropriate as they could allow use of indicated anticoagulation or antiplatelet treatment. Several studies have evaluated septodermoplasty with the largest study(24) in which eighty-six percent of followed patients reported improved QOL, after mean follow-up of 3.75 years. Complications included worsening sinus infections (30%), decreased sense of smell, (58%) and frequent minor side effects, such as crusting and nasal airflow obstruction. Richer and colleagues(26) reported a series of 43 patients undergoing nasal closure, 83% reporting complete cessation of bleeding and no patients requesting reversal of the procedure. The largest study(28) includes 100 patients that underwent nasal closure with 50 of them having pre and post procedure data; ninety-four percent reported complete cessation of the bleeding. A number of surgical variations have been described for both nasal closure and septodermoplasty, though these have not been compared, and therefore clinical decision making should involve a rhinologic surgeon with expertise in these techniques.