Epistaxis (Nosebleed) Management

Recommendations from the Second International HHT Guidelines (2020)

A1: The expert panel recommends that patients with HHT-related epistaxis use moisturizing topical therapies that humidify the nasal mucosa to reduce epistaxis.

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Agreement
Quality of Evidence: Moderate (Agreement 98%)

Topical saline has been shown to reduce epistaxis severity score, compared to baseline, in an RCT of multiple topical therapies (9 Supplement Table 2).


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Agreement
Strength of Recommendation: Strong (Agreement 100%)

Clinical Considerations:
Topical saline (spray or gel) is typically used twice daily.

A2: The expert panel recommends that clinicians consider the use of oral tranexamic acid for the management of epistaxis that does not respond to moisturizing topical therapies.

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Agreement
Quality of Evidence: High (Agreement 92%)

Two RCTs of oral tranexamic acid demonstrated a significant decrease in epistaxis severity(10, 11) with minimal adverse events (Supplement Table 2).


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Agreement
Strength of Recommendation: Strong (Agreement 94%)

Clinical Considerations: Prescribing and safety monitoring guidance for oral tranexamic acid is detailed in (Supplement Table 4)

A3: The expert panel recommends that clinicians should consider ablative therapies for nasal telangiectasias including laser treatment, radiofrequency, electrosurgery, and sclerotherapy in patients that have failed to respond to moisturizing topical therapies.

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Agreement
Quality of Evidence: Moderate (Agreement 83%)

One RCT demonstrated reduced ESS, with sclerotherapy(12).  Multiple uncontrolled series of various ablative therapies demonstrated temporarily reduced epistaxis(13-15).  (Supplement Table 2) (Supplement Table 3)


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Agreement
Strength of Recommendation: Weak (Agreement 94%)

Clinical Considerations: Clinicians and patients should choose the specific ablative therapy based on local expertise, understanding that ablative therapy is a temporizing treatment for epistaxis and perforation of the nasal septum is a known complication of all techniques.

A4: The expert panel recommends that clinicians consider the use of systemic antiangiogenic agents for the management of epistaxis that has failed to respond to moisturizing topical therapies, ablative therapies and/or tranexamic acid.

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Agreement
Quality of Evidence: Moderate (Agreement 92%)

Multiple uncontrolled series of intravenous (IV) bevacizumab have demonstrated reduced epistaxis, improved anemia, reduced transfusion requirements or improved QOL(16-23) (Supplement Table 3).


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Agreement
Strength of Recommendation: Strong (Agreement 82%)

Clinical Considerations: Prescribing and safety monitoring guidance for IV bevacizumab is detailed in Supplement Table 4.  Oral thalidomide can also be considered, though side effects often limit long term use. Risks, and benefits of anti-angiogenic medications should be considered, as well as alternatives, such as septodermoplasty and nasal closure, in these patients. Shared decision making with patients is crucial.

A5: The expert panel recommends that clinicians consider a septodermoplasty for patients whose epistaxis has failed to respond sufficiently to moisturizing topical therapies, ablative therapies, and/or tranexamic acid.

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Agreement
Quality of Evidence: Low (Agreement 92%)

Multiple uncontrolled series of septodermoplasty have demonstrated reduced epistaxis, improved anemia, reduced surgical re-intervention or improved QOL(24-29) (Supplement Table 3).


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Agreement
Strength of Recommendation: Weak (Agreement 88%)

Clinical considerations: Clinicians and patients should consider septodermoplasty when epistaxis affects QOL or is life-threatening, considering risks and benefits, as well as alternatives, such as nasal closure and anti-angiogenic medications. Shared decision making with patients is crucial.

A6: The expert panel recommends that clinicians consider a nasal closure for patients whose epistaxis has failed to respond sufficiently to moisturizing topical therapies, ablative therapies, and/or tranexamic acid.

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Agreement
Quality of Evidence: Moderate (Agreement 86%)

Multiple uncontrolled series of nasal closure have demonstrated reduced epistaxis, (26, 28) (Supplement Table 5)


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Agreement
Strength of Recommendation: Strong (Agreement 82%)

Clinical considerations: Clinicians and patients should consider nasal closure when epistaxis affects QOL or is life-threatening, considering risks and benefits, as well as alternatives, such as septodermoplasty and anti-angiogenic medications.

Shared decision making with patients is crucial.

Currently Recommended from the First International HHT Guidelines (2009)

A7: The expert panel recommends that physicians advise patients with HHT-related epistaxis to use agents that humidify the nasal mucosa to prevent epistaxis.

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Agreement
Level of Evidence: III
Strength of Recommendation: Weak

A8: The expert panel recommends that clinicians refer HHT patients with epistaxis and who desire treatment to otorhinolaryngologists with HHT expertise for evaluation and treatment.

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Agreement
Level of Evidence: III

Strength of Recommendation: Weak

A9: The expert panel recommends that when considering nasal surgery for reasons other than epistaxis, the patient and clinician obtain consultation from an otorhinolaryngologists with expertise in HHT-related epistaxis.

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Agreement
Level of Evidence: III

Strength of Recommendation: Weak

A10: The expert panel recommends that the treatment for acute epistaxis requiring intervention include packing with material or products that have a low likelihood of causing re-bleeding with removal (e.g., lubricated low-pressure pneumatic packing)

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Agreement
Level of Evidence: III

Strength of Recommendation: Weak

Background

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.

Second International Guidelines

Download 2020 HHT Guidelines 

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Agreement