Table of Recommendations

Second International HHT Guidelines and Currently Recommended Clinical Recommendations from the First International HHT Guidelines

Listed below are the clinical recommendations with >=80% consensus at the second International HHT Guidelines. These are followed by the clinical recommendations from the first International Guidelines with >=80% consensus AND which were not re-assessed by the 2019 International Guidelines Working Group.  The expert panel is aware of new evidence and insights regarding some of these existing guidelines and they have been prioritized for updating at the next Guidelines process (Appendix 4).

Epistaxis Management

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

Quality of Evidence: Moderate (Agreement 98%)

Strength of Recommendation: Strong (Agreement 100%)

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.

Quality of Evidence: High (Agreement 92%)

Strength of Recommendation: Strong (Agreement 94%)

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.

Quality of Evidence: Moderate (Agreement 83%)

Strength of Recommendation: Weak (Agreement 94%)

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.

Quality of Evidence: Moderate (Agreement 92%)

Strength of Recommendation: Strong (Agreement 82%)

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.

Quality of Evidence: Low (Agreement 92%)

Strength of Recommendation: Weak (Agreement 88%)

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.

Quality of Evidence: Moderate (Agreement 86%)

Strength of Recommendation: Strong (Agreement 82%)

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HHT Guidelines

A7: The expert panel recommends that physicians advise patients with HHT-related epistaxis to use agents that humidify the nasal mucosa to prevent epistaxis. (Agreement 94%)

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. (Agreement 87%)

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. (Agreement 100%)

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) (Agreement 93%)

Level of Evidence: III

Strength of Recommendation: Weak

 

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HHT Guidelines

 

Gastrointestinal Bleeding Management

B1: The expert panel recommends esophagogastroduodenoscopy as the first line diagnostic test for suspected HHT-related bleeding. Patients who meet colorectal cancer screening criteria and patients with SMAD4-HHT (genetically proven or suspected) should also undergo colonoscopy.

Quality of Evidence: Low (Agreement 82%)

Strength of Recommendation: Strong (Agreement 94%)

 

B2: The expert panel recommends considering capsule endoscopy for suspected HHT-related bleeding, when esophagogastroduodenoscopy does not reveal significant HHT-related telangiectasia.

Quality of Evidence: Low (Agreement 92%)

Strength of Recommendation: Strong (Agreement 88%)

 

B3: The expert panel recommends that clinicians grade the severity of HHT-related GI bleeding and proposes the following framework:

  • Mild HHT-related GI bleeding: Patient who meets their hemoglobin goals* with oral iron replacement.
  • Moderate HHT-related GI bleeding: Patient who meets their hemoglobin goals* with IV iron treatment.
  • Severe HHT-related GI bleeding: Patient who does not meet their hemoglobin goals* despite adequate iron replacement or requires blood transfusions.

* Hemoglobin goals should reflect age, gender, symptoms and comorbidities.

Quality of Evidence: Low (expert consensus) (Agreement 96%)

Strength of Recommendation: Strong (Agreement 96%)

 

B4: The expert panel recommends that endoscopic argon plasma coagulation be only used sparingly during endoscopy.

Quality of Evidence: Low (expert consensus) (Agreement 88%)

Strength of Recommendation: Weak (Agreement 81%)

 

B5: The expert panel recommends that clinicians consider treatment of mild HHT-related GI bleeding with oral antifibrinolytics.

Quality of Evidence: Low (Agreement 94%)

Strength of Recommendation: Weak (Agreement 90%)

 

B6: The expert panel recommends that clinicians consider treatment of moderate to severe HHT-related GI bleeding with intravenous bevacizumab or other systemic anti-angiogenic therapy.

Quality of Evidence: Moderate (Agreement 94%)

Strength of Recommendation: Strong (Agreement 98%)

 

Second HHT Guidelines

Anemia and Anticoagulation

C1: The expert panel recommends that the following HHT patients be tested for iron deficiency and anemia:

●All adults, regardless of symptoms

●All children with recurrent bleeding and/or symptoms of anemia

Quality of Evidence: High (Agreement 98%)

Strength of Recommendation: Strong (Agreement 96%)

 

C2: The expert panel recommends iron replacement for treatment of iron deficiency and anemia as follows:

●Initial therapy with oral iron

●Intravenous iron replacement for patients in whom oral is not effective, not absorbed or not tolerated, or presenting with severe anemia

Quality of Evidence: Moderate (Agreement 88%)

Strength of Recommendation: Strong (Agreement 100%)

 

C3: The expert panel recommends RBC transfusions in the following settings:

●Hemodynamic instability/shock

●Comorbidities that require a higher hemoglobin target

●Need to increase the hemoglobin acutely, such as prior to surgery or during pregnancy

●Inability to maintain an adequate hemoglobin despite frequent iron infusions

Quality of Evidence: Low (Agreement 92%)

Strength of Recommendation: Strong (Agreement 96%)

 

C4: The expert panel recommends considering evaluation for additional causes of anemia in the setting of an inadequate response to iron replacement.

Quality of Evidence: Low (Agreement 100%)

Strength of Recommendation: Strong (Agreement 100%)

 

C5: The expert panel recommends that HHT patients receive anticoagulation (prophylactic or therapeutic) or antiplatelet therapy when there is an indication, with consideration of their individualized bleeding risks; bleeding in HHT is not an absolute contraindication for these therapies.

Quality of Evidence: Low (Agreement 98%)

Strength of Recommendation: Strong (Agreement 98%)

 

C6: The panel recommends avoiding the use of dual antiplatelet therapy and/or combination of antiplatelet therapy and anticoagulation, where possible, in patients with HHT.

Quality of Evidence: Low (expert consensus) (Agreement 83%)

Strength of Recommendation: Weak (Agreement 92%)

 

Second HHT Guidelines

Liver VMs in HHT

D1: The expert panel recommends that screening for liver VMs be offered to adults with definite or suspected HHT.

Quality of Evidence: Low (Agreement 84%)

Strength of Recommendation: Weak (Agreement 93%)

 

D2: The expert panel recommends diagnostic testing for liver VMs in HHT patients with symptoms and/or signs suggestive of complicated liver VMs (including heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension or encephalopathy), using Doppler ultrasound, multiphase contrast CT scan or contrast abdominal MRI for diagnostic assessment of liver VMs.

Quality of Evidence: High (Agreement 98%)

Strength of Recommendation: Strong (Agreement 100%)

 

D3: The expert panel recommends an intensive first-line management only for patients with complicated and/or symptomatic liver VMs, tailored to the type of liver VM complication(s).

The expert panel recommends that HHT patients with high-output cardiac failure and pulmonary hypertension be co-managed by the HHT Center of Excellence AND an HHT cardiologist OR a pulmonary hypertension specialty clinic.

Quality of Evidence: Moderate (Agreement 88%)

Strength of Recommendation: Strong (Agreement 88%)

 

D4: The expert panel recommends that clinicians estimate prognosis of liver VMs using available predictors, to identify patients in need of closer monitoring.

Quality of Evidence: Moderate (Agreement 89%)

Strength of Recommendation: Strong (Agreement 82%)

 

D5: The expert panel recommends considering intravenous bevacizumab for patients with symptomatic high-output cardiac failure due to liver VMs who have failed to respond sufficiently to first-line management.

Quality of Evidence: Moderate (Agreement 98%)

Strength of Recommendation: Strong (Agreement 98%)

 

D6: The expert panel recommends referral for consideration of liver transplantation for patients with symptomatic complications of liver VMs, specifically refractory high-output cardiac failure, biliary ischemia or complicated portal hypertension.

Quality of Evidence: Moderate (Agreement 83%)

Strength of Recommendation: Strong (Agreement 92%)

 

Second HHT Guidelines
D7: The expert panel recommends that liver biopsy be avoided in any patient with proven or suspected HHT. (Agreement 97%)

Level of Evidence: III

Strength of Recommendation: Strong

 

D8: The expert panel recommends that hepatic artery embolization be avoided in patients with liver VMs as it is only a temporizing procedure associated with significant morbidity and mortality. (Agreement 94%)

Level of Evidence: III

Strength of Recommendation: Strong

 

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Pediatric Care

E1: The expert panel advises that diagnostic genetic testing be offered for asymptomatic children of a parent with HHT.

Quality of Evidence: High (Agreement 96%)

Strength of Recommendation: Strong (Agreement 94%)

 

E2: The expert panel recommends screening for pulmonary AVMs in asymptomatic children with HHT or at risk for HHT at the time of presentation / diagnosis.

Quality of Evidence: Moderate (Agreement 94%)

Strength of Recommendation: Strong (Agreement 94%)

 

E3: The expert panel recommends that large pulmonary AVMs and pulmonary AVMs associated with reduced oxygen saturation be treated in children to avoid serious complications.

Quality of Evidence: Moderate (Agreement 98%)

Strength of Recommendation: Strong (Agreement 98%)

 

E4: The expert panel recommends repeating pulmonary AVM screening in asymptomatic children with HHT or at risk for HHT; typically at 5 year intervals.

Quality of Evidence: Low (Agreement 92%)

Strength of Recommendation: Strong (Agreement 86%)

 

E5: The expert panel recommends screening for brain VM in asymptomatic children with HHT, or at risk for HHT, at the time of presentation / diagnosis.

Quality of Evidence: Low (Agreement 86%)

Strength of Recommendation: Strong (Agreement 86%)

 

E6: The expert panel recommends that brain VMs with high risk features be treated.

Quality of Evidence: Low (Agreement 100%)

Strength of Recommendation: Strong (Agreement 98%)

 

Second HHT Guidelines

Pregnancy and Delivery

F1: The expert panel recommends that clinicians discuss pre-conception and pre-natal diagnostic options including pre-implantation genetic diagnosis with HHT affected individuals.

Quality of Evidence: Very Low (Agreement 86%)

Strength of Recommendation: Strong (Agreement 83%)

 

F2: The expert panel recommends testing with unenhanced MRI in pregnant women with symptoms suggestive of brain VMs.

Quality of Evidence: Very Low (Agreement 98%)

Strength of Recommendation: Strong (Agreement 92%)

 

F3: The expert panel recommends that pregnant women with HHT who have not been recently screened and/or treated for pulmonary AVM should be approached as follows:

●In asymptomatic patients, initial pulmonary AVM screening should be performed using either agitated saline transthoracic contrast echocardiography (TTCE) or low-dose non-contrast chest CT, depending on local expertise. Chest CT, when performed, should be done early in the second trimester.

●In patients with symptoms suggestive of pulmonary AVM, diagnostic testing should be performed using low-dose non-contrast chest CT. This testing can be performed at any gestational age, as clinically indicated.      

●Pulmonary AVMs should be treated starting in the second trimester unless otherwise clinically indicated.

Quality of Evidence: Moderate (Agreement 88%)

Strength of Recommendation: Strong (Agreement 83%)

 

F4: The expert panel recommends that pregnant women with HHT be managed at a tertiary care center by a multi-disciplinary team, if they have untreated pulmonary AVMs and/or brain VMs OR have not been recently screened for pulmonary AVMs.

Quality of Evidence: Very Low (Agreement 94%)

Strength of Recommendation: Strong (Agreement 85%)

 

F5: The expert panel recommends not withholding an epidural because of a diagnosis of HHT, and that screening for spinal vascular malformations is not required.

Quality of Evidence: Low (Agreement 98%)

Strength of the Recommendation: Strong (Agreement 92%)

 

F6: The expert panel recommends that women with known, non-high risk brain VMs can labor and proceed with vaginal delivery. Patients may require an assisted second stage on a case by case basis.

Quality of Evidence: Moderate (Agreement 94%)

Strength of the Recommendation: Strong (Agreement 94%)

 

Second HHT Guidelines

Diagnosis of HHT

G1: The expert panel recommends that clinicians diagnose HHT using the Curaçao Criteria or by identification of a causative mutation. (Agreement 82%)

Level of Evidence: III

Strength of Recommendation: Weak

 

G2: The expert panel recommends that clinicians consider the diagnosis of HHT in patients with one or more Curaçao criteria. (Agreement 91%)

Level of Evidence: III

Strength of Recommendation: Weak

 

G3: The expert panel recommends that asymptomatic children of a parent with HHT be considered to have possible HHT, unless excluded by genetic testing. (Agreement 87%)

Level of Evidence: III

Strength of Recommendation: Weak

 

G4: The expert panel recommends that clinicians refer patients for diagnostic genetic testing for HHT (Agreement 80%)

    1. To identify the causative mutation in a family with clinically confirmed HHT

    2. To establish a diagnosis in relatives of a person with a known causative

         mutation, including:

          a. Individuals who are asymptomatic or minimally symptomatic

          b. Individuals who desire prenatal testing

    3. To assist in establishing a diagnosis of HHT in individuals who do not

         meet clinical diagnostic criteria

Level of Evidence: III

Strength of Recommendation: Weak

 

G5: The expert panel recommends that for individuals who test negative for ENG and ACVRL1 coding sequence mutations, SMAD4 testing should be considered to identify the causative mutation. (Agreement 93%)

Level of Evidence: III

Strength of Recommendation: Weak

 

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HHT Guidelines

Brain VMs

H1: The expert panel recommends the use of MRI for brain VM screening in adults with possible or definite HHT using a protocol with and without contrast administration and using sequences that detect blood products, to maximize sensitivity. (Agreement 100%)

Level of Evidence: III

Strength of Recommendation: Weak

 

H2: The expert panel recommends that adults presenting with an acute hemorrhage secondary to a brain VM be considered for definitive treatment in a center with neurovascular expertise. (Agreement 94%)

Level of Evidence: III

Strength of Recommendation: Strong

 

H3: The expert panel recommends that all other adults with brain VMs be referred to a center with neurovascular expertise to be considered for invasive testing and individualized management. (Agreement 84%)

Level of Evidence: III

Strength of Recommendation: Strong

 

H4: The expert panel recommends that pregnant women with suspected or confirmed HHT harboring an asymptomatic brain VM during pregnancy have definitive treatment of their brain VM deferred until after delivery of their fetus. The expert panel recommends that the delivery of the fetus follow obstetrical principles (Agreement 80%)

Level of evidence: III

Strength of Recommendation: Weak

 

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HHT Guidelines

Pulmonary AVMs

I1: The expert panel recommends that clinicians screen all patients with possible or confirmed HHT for pulmonary AVMs. (Agreement 96%)

Level of Evidence: III

Strength of Recommendation: Strong

 

I2: The expert panel recommends that clinicians use transthoracic contrast echocardiography as the initial screening test for pulmonary AVMs. (Agreement 96%)

Level of Evidence: II

Strength of Recommendation: Weak

 

I3: The expert panel recommends that clinicians treat pulmonary AVMs with transcatheter embolotherapy. (Agreement 96%)

Level of Evidence: II

Strength of Recommendation: Strong

 

I4: The expert panel recommends that clinicians provide the following long-term advice to patients with documented pulmonary AVMs (treated or untreated):

    1. Antibiotic prophylaxis for procedures with risk of bacteremia

    2. When IV access is in place, take extra care to avoid IV air

    3. Avoidance of SCUBA diving

(Agreement 87%)

Level of Evidence: III

Strength of Recommendation: Weak

 

I5: The expert panel recommends that clinicians provide long-term follow-up for patients who have pulmonary AVMs, in order to detect growth of untreated pulmonary AVMs and also reperfusion of treated AVMs. (Agreement 100%)

Level of Evidence: II

Strength of Recommendation: Strong

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