7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions : Claire L Shovlin, PhD, FRCP : Lawrence LK Leung, MD : Jennifer S Tirnauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 26, 2022. INTRODUCTION Hereditary hemorrhagic telangiectasia (HHT; also called Osler-Weber-Rendu syndrome) is an autosomal dominant vascular disorder associated with a variety of clinical manifestations including mucocutaneous telangiectasia, epistaxis, gastrointestinal bleeding, and iron deficiency anemia. Arteriovenous malformations (AVMs) commonly occur in the pulmonary, hepatic, and cerebral circulations. This topic review discusses the management of vascular lesions in individuals with HHT, including epistaxis; gastrointestinal lesions; and pulmonary, hepatic, and cerebral AVMs. Other aspects of HHT care are discussed separately: Pathophysiology, epidemiology, and diagnosis (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) Screening for asymptomatic AVMs and testing and counseling of family members (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".) OVERVIEW Definition of terms The following vascular lesions are seen in individuals with HHT: https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 1/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Arteriovenous malformation An arteriovenous malformation (AVM) is an abnormal vascular structure that provides a direct communication between one or more arteries and one or more veins. These may be sacs (eg, for pulmonary AVMs), small collections of intervening vessels (nidal AVMs), or direct high-flow connections between the arterial and venous side (arteriovenous fistulas [AVFs]). AVMs result in arteriovenous shunting. Shunting may also be observed secondary to dilatation of existing normal capillaries (eg, intrapulmonary shunting in the hepatopulmonary syndrome and as part of normal physiologic responses). Telangiectasia A telangiectasia is a small, dilated blood vessel (arteriole, venule, or capillary). The term is descriptive and refers to telangiectasia of many anatomic types and etiologies. HHT telangiectasia usually contain small arteriovenous communications and are commonly located near the surface of skin or mucous membranes. These lesions are not specific for HHT; they can also be seen sporadically in otherwise healthy individuals, associated with other disorders, or as part of a syndrome. Additional vascular lesions are increasingly recognized, some seen more commonly in patients with HHT, and others, such as aneurysms, present at similar or only marginally increased rates to the general population. General principles of management Major management issues in individuals with HHT span the full range of clinical manifestations ( table 1) and have been summarized in International Guidelines published in 2020 [1] and Consensus Statements from the European Reference Network (ERN) and other groups [2-5]. Important general elements include: Patient educational materials for individuals with HHT, and the location of specialized centers for diagnostic testing and management, are available from the websites of Cure HHT, VASCERN (the European Reference Network on Rare Multisystemic Vascular Diseases), and country-specific patient groups. Clinician education regarding the importance of epistaxis as the main cause of anemia, the need for intervention for certain asymptomatic individuals, and the paucity of clinical signs in patients with genetically confirmed HHT with visceral AVMs [6]. HHT vascular lesions may mimic metastases to liver or lung. Individuals with epistaxis (and less frequently, gastrointestinal bleeding) from sites that are accessible can receive dedicated local therapies; however, systemic therapies are sometimes used very successfully. (See 'Epistaxis' below and 'Gastrointestinal lesions' below and 'Hepatic AVMs' below.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 2/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Other localized vascular lesions should be assessed and treated ( table 1). This may require subspecialist management. The interventions used are generally the same as the treatment of the lesion in the absence of HHT. (See 'Therapy for specific vascular lesions and iron deficiency' below.) Systemic treatments may be needed for those with refractory bleeding, usually manifested by requirements for multiple blood transfusions and/or iron infusions. When reviewing evidence for systemic therapies, it is important to prioritize data from randomized trials. Individuals on the placebo arm often experience improvement in symptoms, illustrating the challenges in using observational studies to ascribe benefit [7]. (See 'Tamoxifen and other non-guideline approaches' below and 'Bevacizumab and other systemic antiangiogenic therapies' below.) When anticoagulation or antiplatelet therapy is indicated (for prophylaxis or treatment of thromboembolic or cardiovascular disease), this therapy should not be denied simply due to the HHT diagnosis. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Individuals who require anticoagulation (VTE and AF)'.) An approach to screening for asymptomatic AVMs and other aspects of routine care are discussed separately. It is especially important to identify pulmonary AVMs (PAVMs) to prevent paradoxical emboli, strokes, and brain abscesses. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".) Many management recommendations are based on expert opinion and observational studies; although data from randomized trials are emerging for several areas of management, randomized trials have not delivered statistical support for several proposed treatments, and larger and further studies are underway with results awaited. In the meantime, as described in the sections below, much of expert opinion and practice remains guided by observational studies [1,3-5]. The uniformity of expert opinion varies depending on the clinical situation and prevailing health care practices. The second International HHT Guideline, published in 2020 by an international consensus group, was updated to take into account changes in evidence and advances in genetic testing [1]. The first International Guideline for the management of HHT was developed by the same group in 2006, made available online in 2007, and published in print in 2011 [8]. The 2020 International Guideline addressed six topics: epistaxis, gastrointestinal bleeding, anemia/anticoagulation, hepatic vascular malformations, pediatrics, and pregnancy [1]. This Guideline was more nuanced in separating the severity of indications for elements of care https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 3/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate proposed in the first Guideline (presenting in a stepwise fashion according to the severity of the disease), and also incorporated some new recommendations. For evaluation and therapy, the main new item in the 2020 Guideline was the incorporation of systemic antiangiogenic therapies into the algorithms for epistaxis, gastrointestinal bleeding, and severe hepatic AVMs (data on antiangiogenic therapy in HHT was not available when the first Guideline was generated in 2006). (See 'Bevacizumab and other systemic antiangiogenic therapies' below.) While previous guidelines recommended referral to specialists with relevant expertise (eg, otorhinolaryngologists, centers with neurovascular expertise), the 2020 Guideline detailed structured approaches recommended for the specialty management. Anemia was discussed as a separate topic. Previous guidelines had discussed management with oral and intravenous iron: the 2020 Guideline included a specific recommendation for red blood cell transfusions in the settings of hemodynamic instability/shock; comorbidities that require a higher hemoglobin target; need to increase the hemoglobin acutely, such as prior to surgery or during pregnancy; and/or inability to maintain an adequate hemoglobin despite frequent iron infusions. (See 'Iron deficiency and iron deficiency anemia' below.) Consensus statements on good practice in HHT have also been developed by the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases ( VASCERN). This group has identified core Outcome Measures suitable to be implemented by all clinicians evaluating a patient with HHT: PAVM screening, antibiotic prophylaxis prior to dental and surgical procedures for those with PAVMs, epistaxis advice, assessment of iron deficiency, and advice on pregnancy [3]. Subsequent manuscripts include evidence from HHT patients across the ERN [3,4,9,10]. Frameworks published in 2022 include guidance for general health care practitioners reviewing HHT patients in non-specialty care as well as providing summary data and pathophysiological integrations for HHT specialists [2]. Educational materials for patients with HHT and the location of specialized centers for diagnostic testing and management are available from the websites of Cure HHT, VASCERN, and country-specific patient groups. THERAPY FOR SPECIFIC VASCULAR LESIONS AND IRON DEFICIENCY Epistaxis Epistaxis is the most common site of blood loss in HHT, affecting more than 90 percent of patients. Very high proportions experience epistaxis on a daily or near-daily basis, https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 4/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate and the iron losses are often sufficient to cause iron deficiency anemia, even in the absence of additional gastrointestinal bleeding. Management of epistaxis and iron deficiency anemia are therefore cornerstones of HHT management. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Epistaxis'.) The 2020 International Guideline provides a stepwise approach to treatment of epistaxis, in the following sequence [1]: Topical therapies Oral tranexamic acid Ablative therapies by otorhinolaryngologists Systemic antiangiogenic therapy (eg, bevacizumab) Septal dermatoplasty Young's procedure (nostril closure) As discussed below, there is evidence from randomized controlled trials for tamoxifen and tranexamic acid in HHT, and randomized trials are especially important in HHT (see 'General principles of management' above). Although tamoxifen was not addressed in the 2020 guideline, we suggest tamoxifen for individuals who require systemic therapy. Tranexamic acid is another reasonable option. (See 'Tamoxifen and other non-guideline approaches' below and 'Oral tranexamic acid' below.) There has also been widespread adoption of bevacizumab, and two further drugs (raloxifene and thalidomide) have received European Medicine Agency orphan drug designation for use in HHT, despite not being the most commonly used agents and no supportive evidence from randomized trials. Bevacizumab can be useful for individuals with severe bleeding. However, the transiency of some responses, lack of randomized trial data, and adverse effects should also be considered. (See 'Bevacizumab and other systemic antiangiogenic therapies' below.) The decision to use particular approaches depends on risk-benefit evaluations individualized to incorporate potential benefits and risks for the specific patient, as discussed in more detail below. Potential beneficial effects from systemic agents need to be balanced against the risks, and this is ideally conducted by clinicians with expertise using these agents in HHT. When weighing risks and benefits, there are few randomized trials to guide care. Early randomized trials provided evidence of benefit for the following: Estrogen-progesterone [11] Tamoxifen [12,13] Tranexamic acid [14,15] https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 5/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Systemic propranolol [16] However, other randomized trials have not shown convincing evidence of benefit in the treatment arm [7,17-22]. For two of the trials, there was marked improvement in the placebo arm, reflecting the benefit of saline and gel administration [17,18]. The degree of ill health and/or compromised quality of life due to HHT-associated bleeding not responding to all other measures means that the risks of systemic therapies may be considered justifiable [9]. However, it is important to recognize that most HHT patients with nosebleeds and anemia will not require such treatments that should be reserved for severe cases. Although all drugs have their specific side effect profiles, the risk of venous thromboembolism (VTE) requires a special note. Concerns about VTE with systemic therapies have led to the development of investigational topical agents (see 'Topical therapies' below). The systemic agents used to treat HHT-related epistaxis also increase the risk of VTE; individuals who develop VTE would require full anticoagulation with its attendant risks [23-25]. Across Europe, these agents are therefore generally avoided in patients with a prior history of VTE and/or those at particularly high risk of cerebral sequelae (eg, due to concurrent atrial fibrillation). Topical therapies Additional information about local therapies for the management of epistaxis is presented separately. (See "Management of epistaxis in children" and "Approach to the adult with epistaxis".) In HHT, accumulating evidence encourages the use of local (topical) preventive therapies [1]: Nasal humidification Ointments Saline spray [17] Gel [18] These therapies are essentially free of significant adverse effects, although occasional individuals report that they seem to precipitate their nosebleeds, in which case they should be discontinued. Saline nasal sprays Saline nasal sprays can be used to prevent drying, especially during winter and in dry environments such as airplanes. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Air travel'.) Saline nasal sprays demonstrated significant benefits in two trials in which they were used as placebo: https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 6/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate In one trial from 2016 involving 80 patients with HHT randomly assigned to receive intranasal bevacizumab or a saline nasal spray, the epistaxis severity score (ESS) in the 27 patients receiving nasal saline was reduced from 5.7 (95% CI 5.0-6.3) to 3.7 (95% CI 3.2-4.3) [7]. Other studies have demonstrated that the minimally important difference in the ESS is 0.7 [26]. In a survey of 649 patients with HHT and epistaxis, there were positive (beneficial) scores for improvement of epistaxis with saline treatments, room humidification, and nasal lubrication [27]. In another trial from 2016 involving 121 patients with HHT who were randomly assigned to receive one of several nasal sprays (active agents bevacizumab, estriol, tranexamic acid, or saline [placebo]), there were no significant between-group differences [17]. Thermosensitive gel In a randomized trial of 27 patients, benefit was seen in the placebo arm, which used a thermosensitive gel [18]. The median reduction in ESS was 1.96 (range, -0.91 to 5.98), and 9 of 12 participants (75 percent) receiving the placebo gel experienced a clinically meaningful improvement in ESS. Topical beta blockers Topical betablockers have been shown to demonstrate efficacy in some but not all randomized controlled trials: Propranolol demonstrated efficacy in a 2020 trial in 20 participants with moderate- severe HHT-related epistaxis who were randomly assigned to eight weeks of propranolol gel (1.5%) or placebo [16]. Dosing used 0.5 mL, applied to each nostril twice daily; and propranolol was continued for eight weeks in an open-label study. For the propranolol group, the ESS improved significantly (-2.03 1.7, versus -0.35 0.68 for the placebo group, p = 0.009). Hemoglobin levels also improved significantly (10.5 2.6 to 11.4 2.02 g/dL, p = 0.009); and intravenous iron and blood transfusion requirement decreased. The change in nasal endoscopy findings was not significant. During the open-label period, the ESS score improved significantly in the former placebo group (-1.99 1.41, p = 0.005). There was not a significant benefit in a trial in which 27 participants were randomly assigned to use timolol gel or placebo gel; the median change in ESS was 2.32 (range, 0.22 to 5.97) with timolol gel versus 1.96 (-0.91 to 5.98) with placebo [18]. A clinically meaningful improvement in ESS was experienced by 9 of 11 (82 percent) in the timolol gel group versus 9 of 12 (75 percent) with placebo. In another trial that randomly assigned 58 individuals to receive timolol nasal spray (0.25 mg in each nostril twice a https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 7/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate day for 28 consecutive days) or placebo, ESS did not improve with timolol administration [19]. Topical estrogen or other agents A 2016 trial in which 121 patients were assigned to apply a 0.1 percent estriol ointment (a low potency metabolite of estradiol), topical bevacizumab, topical tranexamic acid, or placebo to the nasal mucosa found no benefit of any of the active treatments [17]. However, the study was not sufficiently powered to rule out an effect, and a larger study of topical therapy may be warranted. A 2018 meta-analysis that included eight randomized placebo-controlled clinical trials found that submucosal (delivered endoscopically) bevacizumab and oral tamoxifen delivered benefit [28]. All of the nasal sprays (bevacizumab, tranexamic acid, or estrogen) showed a trend towards reduced frequency of epistaxis that did not reach statistical significance. Despite these negative findings, responses vary in different individuals, and it is not possible to predict who will respond particularly well to a given intervention. A 2020 randomized trial found that tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment [20]. Emergency nasal packing may be required for severe hemorrhage. (See "Approach to the adult with epistaxis", section on 'Nasal packing'.) Oral tranexamic acid Tranexamic acid is proposed in the 2020 HHT guidelines to be second- line therapy for HHT nosebleeds that do not respond to topical therapies. It can be taken orally two to three times per day. Randomized trial evidence for efficacy of tranexamic acid with long-term use in HHT includes the following: In the 2014 ATERO trial, 118 individuals with HHT who had epistaxis for more than 60 minutes or 28 days in a month were randomly assigned to receive placebo or tranexamic acid (1.5 g orally twice per day for three months) followed by crossover to the other arm [14]. Compared with placebo, tranexamic acid was associated with a reduced duration of nosebleeds (106 versus 129 minutes per month) but no change in the number of nosebleeds (mean, 23 versus 22 per month). A randomized crossover trial from 2014 in which 22 patients received placebo or tranexamic acid, 1 g orally three times a day for three months, also found a significant reduction in nosebleeds with tranexamic acid, although hemoglobin levels were not improved [15]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 8/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Not all experts agree with such widespread use of tranexamic acid, given the generally lifelong nature of HHT nosebleeds and the possibility of side effects not captured by short-term clinical trial follow-up. In our experience, VTE has developed in patients with HHT, and ischemic strokes have occurred in patients with HHT and pulmonary AVMs (PAVMs) [24,29]. Aminocaproic acid is an antifibrinolytic agent with a similar mechanism of action as tranexamic acid, but the published clinical experience with aminocaproic acid in HHT is much less extensive [30]. Ablative therapies For patients who continue to experience significant nosebleeds, review by an ear nose and throat (ENT) surgeon with expertise in this area is advisable to optimize interventional treatments. Dedicated local ENT treatments are generally directed to patients experiencing frequent epistaxis or less frequent massive hemorrhages [31]. In one survey, 326 of 666 unselected respondents with HHT (49 percent) required specialist invasive treatments, often requiring multimodality therapy [27]. Different types of laser or argon plasma coagulation devices are available, with the choice of method depending on operator preference and availability. Laser therapy is generally preferred over cauterization, since cauterization can damage the nasal mucosa, which may prompt vascular regrowth; however, if cauterization is the only therapy available, it can have beneficial effects [27]. In a survey comparing 267 international HHT users of cauterization and 221 users of laser therapy, laser therapy was reported to be beneficial more frequently than cauterization [27]. Sclerotherapy is another treatment that may be effective. A randomized crossover trial involving 17 patients with HHT and epistaxis found that sclerotherapy with sodium tetradecyl sulfate resulted in a greater reduction in ESS than standard care (moisturization, cautery) [32]. A retrospective study evaluating 67 patients with HHT found that use of sclerotherapy with sodium tetradecyl sulfate resulted in similar efficacy in controlling epistaxis as laser cautery, with fewer procedures required [33]. However, the otorhinolaryngology experts within the European Reference Network have made the point that sclerotherapy carries well-documented risks of adverse events including blindness in the non-HHT population, and full-patient counseling seems appropriate [2]. Coblation therapy (a term derived from the words "controlled ablation") is another treatment reported to be effective; it involves use of radiofrequency ablation at low temperatures to remove problematic tissue. In a study that followed 57 patients with HHT who underwent 150 coblation treatments over the course of 12 years, the average duration of effectiveness was 25 months (range 1 to 86 months) [34]. Of the 26 patients (46 percent) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 9/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate who underwent multiple coblation treatments, the overall average duration of coblation effectiveness was 16.4 months (range, 1 to72 months). Bevacizumab and other systemic antiangiogenic therapies Bevacizumab Bevacizumab is an antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF); it has been tested in retrospective studies of patients with HHT who have significant chronic blood loss (from epistaxis or gastrointestinal lesions) and/or high- output heart failure. It can be very useful for individuals with severe bleeding. However, some responses do not persist, and some individuals discontinue therapy due to adverse events. Additionally, evidence for efficacy only includes observational studies; randomized trial evidence is lacking. The second International HHT Guideline reports multiple uncontrolled series that demonstrated intravenous bevacizumab reduced epistaxis, improved anemia, reduced transfusion requirements, or improved quality of life [1,35-43]. Further observational studies and surveys have been published since those reviewed in the Guideline [44]. At the same time, adverse events have been reported with the use of these therapies [9,45]. Randomized trials are needed. While results of randomized trials are awaited, antiangiogenic therapies were prominent in the recommendations from the second International HHT Guideline recommendations for epistaxis and gastrointestinal bleeding [1]. Evidence from some of the larger studies in severely ill individuals includes the following: A multicenter retrospective study from 2021 that included data from 238 individuals with HHT treated with systemic bevacizumab found favorable safety and efficacy profiles [46]. Dosing protocols varied; the majority received four to six treatments of 5 mg/kg every two weeks, followed by maintenance treatments on a regular schedule (5 mg/kg once every 4 to 12 weeks). Responses were apparent within three months; hemoglobin levels increased by a mean of 3.2 g/dL, the mean ESS decreased by 3.4 points, and the median number of transfusions decreased from six units in six months to zero. In patients who required intravenous iron infusions, the number of infusions decreased from eight infusions in six months to two. Adverse effects included hypertension in 18 percent, fatigue in 10 percent, proteinuria in 9 percent, myalgia or arthralgia in 6 percent, and venous thromboembolism in 2 percent (none fatal). Five percent discontinued bevacizumab for adverse events. Previous smaller studies, some from the same authors who contributed to the 2021 study above, had also suggested efficacy [35-37,47]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 10/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Adverse effects were evaluated in a 2019 study by the European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) in 69 individuals with HHT who were treated with bevacizumab for a mean of 11 months for bleeding or high-output cardiac failure due to hepatic AVMs [9]. Adverse events were reported in 33 patients, more commonly in females (27 adverse events in 46 women versus 6 events in 23 men). The most common of these were joint pain (10 percent), headache (4 percent), and proteinuria (3 percent). Bleeding occurred in two patients (3 percent); one was an episode of grade 3 gastrointestinal bleeding and one was a fatal event of catastrophic hemoptysis from a known but not monitored PAVM. This was considered possibly related to bevacizumab, as spontaneous rupture of PAVMs is highly unusual outside of pregnancy or pulmonary hypertension, which were absent in this individual. Across the ERN, bevacizumab is considered to be a choice of last resort in extremely ill individuals with compromised quality of life, based on the evidence available, which does not include randomized trials, and the known adverse effects in HHT and other settings [9]. Other potential toxicities of bevacizumab identified in the general population (including cardiovascular effects [hypertension, thromboembolism, left ventricular dysfunction], non- cardiovascular effects [proteinuria, bleeding, delayed wound healing, gastrointestinal perforation, fatigue, and dysphonia], and fatal adverse events) are presented in more detail separately. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects" and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects".) IMiDs Thalidomide and lenalidomide have antiangiogenic and immunomodulatory properties [48-51]. There have not been randomized controlled trials of these drugs in HHT. A 2018 systematic review of observational studies found an association between the use of low-dose thalidomide and reduced frequency and duration of epistaxis and need for transfusions [52]. Thalidomide had previously received EMA orphan drug designation for HHT [53,54]. This was based on two small series of individuals with HHT (12 and 7 patients) [48,55]. Patients reported reductions in epistaxis, but many patients (approximately two- thirds and one-third, respectively) discontinued the drug due to side effects that included drowsiness, peripheral neuropathy, nausea, and constipation. Only a minority of patients continued taking thalidomide, primarily due to these side effects [48]. The safety of thalidomide in HHT was specifically evaluated by the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) [9]. Sixty-seven HHT patients received thalidomide, all for bleeding, and for a mean of 13.4 months, totaling 75 person-years of treatment. Adverse events related to thalidomide were reported in 34 individuals (51 percent), with an average incidence rate of 45.3 per 100 person-years. These https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 11/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate were seen at similar rates in males and females. They were more common in individuals with an ENG mutation than an ACVRL1 mutation (all 17 with ENG versus 14 of 34 [41 percent] with ACVRL1). The most common reports were of peripheral neuropathy (18 percent), drowsiness (12 percent), and dizziness (9 percent). Three fatal, adverse events were possibly related to thalidomide (average incidence rate: 4 per 100 person-years). As noted above, systemic therapies have demonstrated adverse effects of which the clinician and patient should be aware. Individuals with HHT who have a history of thromboembolic disease are excluded from clinical trials using these agents [14,38]. Clinical studies using systemic bevacizumab in HHT have also excluded individuals with cerebral arteriovenous malformations (AVMs), thrombocytopenia, or anticoagulant therapy [38]. The use of these drugs remains off-label, and reported experience is still very limited. A number of additional antiangiogenic and other agents have appeared promising in uncontrolled studies, case reports, or preclinical models. Examples include the VEGF inhibitor pazopanib and the immunosuppressive agents sirolimus and interferon [56-60]. It has been suggested that their use should be restricted to selected, consenting individuals in randomized trials conducted at experienced HHT centers, due to the lack of evidence for benefit from randomized trials, potential side effects, and lack of long-term safety and efficacy data [61]. Further ENT options recommended in international guidelines Other directed therapies include septodermoplasty and/or unilateral or bilateral surgical closure of the nostrils [31,62-67]. These invasive treatments are almost always used in patients who have also received laser therapy and/or cauterization [27,31]. Young's procedure (bilateral surgical closure of the nostrils) has not been evaluated in a randomized trial, but as published in a series of 100 cases, many seen by us in subsequent years, it can have remarkable long-term success in alleviating major nosebleeds and reversing transfusion dependency, as long as there is complete closure of nasal flow [68]. However, a small proportion of patients cannot tolerate the procedure and request reversal, and a larger number decline as they are concerned about the implication of anosmia and mouth breathing. Some patients have been treated with submucosal injection of bevacizumab at the time of laser therapy; long-term results of this approach are awaited [69,70]. Tamoxifen and other non-guideline approaches Additional elements that can be incorporated as part of general care include: Dietary changes for prevention HHT nosebleeds usually come in clusters and vary in severity over a lifetime. A proportion of people with HHT (we estimate approximately one in https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 12/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate three) may be able to identify dietary triggers of nosebleeds that can be avoided without detrimentally impacting their lifestyle [27,62,71]. We suggest keeping a food diary of items ingested in the hours immediately prior to an unusually severe bleed to aid identification of potential precipitants. Avoidance of over-the-counter supplements Caution with over-the-counter dietary supplements offers another opportunity to avoid potential precipitants. An example is fish oil supplements, for which antiplatelet activity is not generally appreciated [72]. (See "Fish oil: Physiologic effects and administration".) For individuals who require systemic therapy, the 2020 International HHT Guideline discussions did not incorporate tamoxifen (with evidence from randomized trials) and the two European Medicines Agency (EMA)-recommended drugs raloxifene and thalidomide. Tamoxifen A 2018 meta-analysis of eight randomized placebo-controlled trials demonstrated that only tamoxifen was superior to placebo, reducing both the frequency and the severity of epistaxis [28]. Tamoxifen appears to be well tolerated, has evidence of efficacy from a double-blind, randomized controlled trial, and is our first treatment of choice when a systemic agent is used for treating epistaxis. In a 2018 meta-analysis of randomized, placebo-controlled trials, tamoxifen was the only systemic agent shown to be superior to placebo; it reduced epistaxis severity and frequency [28]. Tamoxifen also has a favorable side effect profile compared with tranexamic acid, bevacizumab, and raloxifene (wider HHT population use of raloxifene is awaited). However, tamoxifen would not be recommended for someone with a prior history of VTE, atrial fibrillation, or similar higher risk-factor status for venous or arterial thromboembolism. (See "Managing the side effects of tamoxifen and aromatase inhibitors".) A benefit from tamoxifen was demonstrated in a 2009 trial that randomly assigned 25 individuals with HHT (men and women) to receive placebo or tamoxifen (20 mg daily) for six months [12]. Compared with placebo, tamoxifen was associated with a reduction in epistaxis, based on self-report and nasal endoscopy (improvement in 18 versus 90 percent). Some individuals assigned to tamoxifen also had an improvement in hemoglobin level or reduction in transfusion requirements. In an extended follow-up of patients completing the trial arm, in a total of 46 patients with mean 23.4 months of treatment, there were improvements in bleeding score, quality-of-life score, and hemoglobin concentration; none required blood transfusions [13]. These and other extended follow-up studies, as well as our experience, suggest sustained benefits from tamoxifen, and therapy has been well tolerated [13,23,73]. In contrast to other agents discussed below, we have yet to see VTE developing in HHT patients using tamoxifen [23,73]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 13/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Premenopausal women taking tamoxifen should be aware of the effects on other organ systems. (See "Managing the side effects of tamoxifen and aromatase inhibitors".) Raloxifene Raloxifene is a selective estrogen receptor modulator (SERM) that has received European Medicine Agency (EMA) orphan drug designation for HHT based on a small pilot study [74,75]. There is no evidence from randomized trials in HHT. Raloxifene is associated with an increased risk of VTE events, particularly during the first four months of treatment, and is contraindicated in people with a history of VTE, hepatic impairment, cholestasis, severe renal impairment, unexplained uterine bleeding, or endometrial cancer. Estrogens High-dose estrogens have been beneficial in the setting of gastrointestinal bleeding from AVMs (see 'Gastrointestinal lesions' below); however, we do not use high- dose estrogens due to their side effect profiles, particularly the increased risk of VTE. The 50 mg estradiol dose that was effective in one study is not tolerated by men, and we consider the risk of VTE too great to use systemic estrogens [11]. N-acetylcysteine A pilot study in 43 patients suggested a possible benefit of N- acetylcysteine [76]. Pazopanib A retrospective review of 13 patients who received pazopanib for transfusion- dependent anemia due to HHT bleeding reported that all 13 became transfusion independent, with evidence for reduction in ESS, decreased intravenous iron use, and improvement in hemoglobin [77]. Compared with pretreatment hemoglobin, those treated with pazopanib for 12 months had an increase in their mean hemoglobin by 4.8 g/dL (95% CI 3.6-5.9), from 7.8 to 12.7 g/dL, and decreased mean ESS by 4.77 points (95% CI 3.11-6.44 points; from 2.43 to 7.20 points). As stated by the authors, these findings require confirmation in a randomized trial. Oral itraconazole In an observational assessment of 21 patients treated with oral itraconazole, four discontinued therapy due to side effects; the remaining 17 had a decrease in mean ESS from 6.0 to 3.8 points (IQR decreased from 5.1-7.2 to 3.1-5.2) [78]. Hemoglobin levels did not change significantly. Gastrointestinal lesions Gastrointestinal lesions in HHT are common (seen in up to 20 percent of patients), but in the majority of cases, treatment is not required, as iron deficiency is primarily due to under-replacement of iron losses from nosebleeds. That said, a small population of patients with HHT have very severe, recurrent gastrointestinal bleeding, and some suggest this is more common in patients with SMAD4 HHT. (See "Hereditary hemorrhagic