Overview of systemic medical therapies for the treatment of bleeding in HHT
| Agent . | Mechanism of action . | Route of administration . | Primary clinical evidence . | Comments . |
|---|---|---|---|---|
| Primary systemic therapies (agents with robust evidence for safety and effectiveness) | ||||
| Tranexamic acid | Antifibrinolytic, displaces plasminogen from fibrin, and inhibits proteolytic activity of plasmin | Oral or IV (emergent situations) | Gaillard et al, 201435, Geisthoff et al, 201436, Zaffar et al, 201537 Beckman et al, 202038 | Largest published study to date included 118 patients with HHT (RCT) Data demonstrates significant improvements in epistaxis severity but not hemoglobin or hematologic support requirements Most common adverse events in patients with HHT include diarrhea (18%), other gastrointestinal disorders (10%), and vertigo (4%). None of the primary evidence in HHT suggests an increased venous thromboembolic risk with daily dosing in the 3-4 g range (over 3-4 divided doses), including at extended treatment durations longer than a year. Major trials were done with tranexamic acid; however, observational studies37,55 include patients treated with ε-aminocaproic acid and the 2 agents are considered generally interchangeable (although, of note, tranexamic acid does have a longer half-life and is optimally dosed 2-3 times daily whereas ε-aminocaproic acid is optimally dosed 3-4 times daily in HHT) |
| Pomalidomide | Antiangiogenic, immunomodulatory imide drug believed to suppress production of VEGF-A, basic fibroblast growth factor, angiopoietins, and other angiogenic growth factors,56,57 and improve vessel wall integrity in telangiectasias58 | Oral | Al-Samkari et al, 2023 (PATH-HHT)45 Samour et al, 201659 | Largest published study to date (PATH-HHT; ClinicalTrials.gov identifier: NCT03910244) included 144 patients with HHT (RCT) Data demonstrate significant and impactful improvements in ESS and HHT-specific HRQoL, along with improvements in hemoglobin, hematocrit, and mean corpuscular volume Most common side effects in patients with HHT include constipation/diarrhea, mild-to-moderate neutropenia, and rash, all of which occurred in ∼30%-50% of patients receiving pomalidomide; venous thromboembolism was rare and occurred in a similar proportion of patients in both pomalidomide and placebo arms in PATH-HHT |
| Bevacizumab | Antiangiogenic, monoclonal antibody that binds to, and inhibits action of, VEGF-A | IV | Al-Samkari et al, 2021 (InHIBIT-Bleed)46, Dupuis-Girod et al, 202360, Albitar et al, 202061, Al-Samkari et al, 202062, Al-Samkari et al, 201963 Iyer et al, 201841 | Largest published study to date (InHIBIT-Bleed) included 238 patients with HHT (observational study); no adequately powered prospective trial has yet been completed, although phase 2 NIH-sponsored TRUST-HHT study (ClinicalTrials.gov identifier: NCT04404881, anticipated recruitment 33 patients) is ongoing Data demonstrate significant and impactful improvements in hemoglobin, iron infusion requirements, red cell transfusion requirements, and ESS Most common adverse events in patients with HHT include hypertension (18%), fatigue (10%), and proteinuria (9%); venous thromboembolism observed in ∼10% of patients with metastatic cancer receiving bevacizumab with cytotoxic chemotherapy, vs 2% in patients with HHT (in InHIBIT-Bleed study), a number similar to the pomalidomide and placebo arms of the PATH-HHT RCT |
| Salvage systemic therapies (agents with limited evidence for safety and effectiveness) | ||||
| Pazopanib | Antiangiogenic and small-molecule VEGF receptor tyrosine kinase inhibitor | Oral | Parambil et al, 202164 Faughnan et al, 201965 | Largest published study to date included 13 patients with HHT (observational study); no adequately powered prospective trial has yet been completed, although US Department of Defense–sponsored phase 2/3 study (ClinicalTrials.gov identifier: NCT03850964, anticipated recruitment 70 patients) is ongoing Currently has breakthrough designation from US FDA for treatment of bleeding in HHT Limited data suggest significant improvements in hemoglobin, iron infusion requirements, red cell transfusion requirements, and ESS Limited data suggest common side effects in patients with HHT include hypertension, lymphocytopenia, and fatigue Data too limited to evaluate thromboembolic risk in HHT |
| Thalidomide | Antiangiogenic, immunomodulatory imide drug that suppresses production of VEGF-A, basic fibroblast growth factor, angiopoietins, and other angiogenic growth factors,56,57 and improves vessel wall integrity in telangiectasias58 | Oral | Invernizzi et al, 201547, Hosman et al, 201548, Baysal et al, 201949 Fang et al, 201750 | Largest published study to date included 31 patients with HHT (prospective) Limited data suggest significant improvements in epistaxis severity, hemoglobin, and red cell transfusion requirements Most common adverse events in patients with HHT include constipation (71%), drowsiness (21%), and elevation of thyroid-stimulating hormone (18%) Data too limited to evaluate thromboembolic risk in HHT, although in patients with multiple myeloma, clinical trials have demonstrated a much higher thromboembolic risk with thalidomide than pomalidomide Peripheral neuropathy, which may be irreversible, is common with thalidomide treatment (and very rare with pomalidomide treatment). The risk of peripheral neuropathy increases with ongoing duration of thalidomide exposure; up to ∼15% of patients with HHT developed peripheral neuropathy within the first 6 months of thalidomide treatment in a prospective clinical trial. |
| Octreotide, lanreotide | Somatostatin analogs that reduce splanchnic blood flow, slowing chronic gastrointestinal bleeding | Subcutaneous Intramuscular IV (emergent situations) | Torres-Iglesias et al, 202366 Kroon et al, 201967 | Largest published study to date included 67 patients with HHT (observational) No impact on epistaxis Limited data suggest significant improvements in hemoglobin and red cell transfusion requirements in patients with gastrointestinal bleeding Data too limited to evaluate adverse events in HHT, but largest published study reported diarrhea and/or abdominal pain in 24%, and discontinuation of treatment because of adverse events in 18% |
| Other notable systemic agents (novel/investigational and repurposed) | ||||
| Tacrolimus | Immunosuppressant, may potentiate the ALK1 pathway68 and possibly stimulate endoglin and ALK1 expression by endothelial cells69 | Oral | Hessels et al, 202270 | Largest published study to date included 25 patients with HHT (prospective); phase 2 study (ClinicalTrials.gov identifier: NCT04646356, anticipated recruitment 30 patients) in HHT, currently ongoing Limited data suggest significant improvements in ESS, hemoglobin, and red cell transfusion requirements Most common adverse events in patients with HHT include headache (40%), abdominal pain (32%), and diarrhea (32%) |
| Sirolimus | Immunosuppressant, inhibitor of mTOR, which is downstream of PI3K and AKT, potentially correcting overactivation of VEGFR271 | Oral | No study in HHT∗ published to date | Pilot study (ClinicalTrials.gov identifier: NCT05269849, anticipated recruitment 10 patients) in HHT, ongoing |
| VAD044 | Antiangiogenic, small-molecule allosteric inhibitor of AKT1, which is critical in vascular development and endothelial cell homeostasis72 | Oral | Investigational, no study published to date | Phase 1b VAD044002 study (ClinicalTrials.gov identifier: NCT05406362, anticipated recruitment 80 patients) in HHT, currently ongoing |
| Nintedanib | Antiangiogenic, small-molecule VEGF receptor tyrosine kinase inhibitor | Oral | No study in HHT∗ published to date | Two phase 2 studies (ClinicalTrials.gov identifier: NCT03954782, anticipated recruitment 30 patients and NCT04976036, anticipated recruitment 48 patients) in HHT, currently ongoing |
| Systemic agents not recommended for use | ||||
| Estrogens/ SERMs (tamoxifen, raloxifene, bazedoxifene) | Estrogenic compounds that increase circulating levels of procoagulant factors and improve vascular integrity73 | Oral IV (emergent situations) | Vase, 198174, van Cutsem et al, 199075, Yaniv et al, 200976 Yaniv et al, 201177 | Small studies, mixed results; negative RCT of systemic estrogen, RCT of tamoxifen with mixed results (reductions in visible blood and blood clots on nasal endoscopy but no improvement in hemoglobin); minimal data on other SERMs Feminizing effects (eg, gynecomastia) in male patients Known, well-defined increase in thromboembolic risk that is synergistic with other venous thromboembolic risk factors; risk of breast and/or uterine cancers given requirement for prolonged use Given the aforementioned, not recommended for use to treat bleeding in the most updated version of the International HHT Guidelines |
| Doxycycline | Tetracycline antibiotic with matrix metalloproteinase inhibitory effects,78 theorized to potentially have antiangiogenic properties | Oral | McWilliams et al, 202279 Faughnan et al, 202380 | Two RCTs with unambiguously negative results; no significant improvement in ESS, hemoglobin, hematologic support requirements, or any other primary or secondary end point in either trial Therefore, no indication for use to treat bleeding in HHT |
| Agent . | Mechanism of action . | Route of administration . | Primary clinical evidence . | Comments . |
|---|---|---|---|---|
| Primary systemic therapies (agents with robust evidence for safety and effectiveness) | ||||
| Tranexamic acid | Antifibrinolytic, displaces plasminogen from fibrin, and inhibits proteolytic activity of plasmin | Oral or IV (emergent situations) | Gaillard et al, 201435, Geisthoff et al, 201436, Zaffar et al, 201537 Beckman et al, 202038 | Largest published study to date included 118 patients with HHT (RCT) Data demonstrates significant improvements in epistaxis severity but not hemoglobin or hematologic support requirements Most common adverse events in patients with HHT include diarrhea (18%), other gastrointestinal disorders (10%), and vertigo (4%). None of the primary evidence in HHT suggests an increased venous thromboembolic risk with daily dosing in the 3-4 g range (over 3-4 divided doses), including at extended treatment durations longer than a year. Major trials were done with tranexamic acid; however, observational studies37,55 include patients treated with ε-aminocaproic acid and the 2 agents are considered generally interchangeable (although, of note, tranexamic acid does have a longer half-life and is optimally dosed 2-3 times daily whereas ε-aminocaproic acid is optimally dosed 3-4 times daily in HHT) |
| Pomalidomide | Antiangiogenic, immunomodulatory imide drug believed to suppress production of VEGF-A, basic fibroblast growth factor, angiopoietins, and other angiogenic growth factors,56,57 and improve vessel wall integrity in telangiectasias58 | Oral | Al-Samkari et al, 2023 (PATH-HHT)45 Samour et al, 201659 | Largest published study to date (PATH-HHT; ClinicalTrials.gov identifier: NCT03910244) included 144 patients with HHT (RCT) Data demonstrate significant and impactful improvements in ESS and HHT-specific HRQoL, along with improvements in hemoglobin, hematocrit, and mean corpuscular volume Most common side effects in patients with HHT include constipation/diarrhea, mild-to-moderate neutropenia, and rash, all of which occurred in ∼30%-50% of patients receiving pomalidomide; venous thromboembolism was rare and occurred in a similar proportion of patients in both pomalidomide and placebo arms in PATH-HHT |
| Bevacizumab | Antiangiogenic, monoclonal antibody that binds to, and inhibits action of, VEGF-A | IV | Al-Samkari et al, 2021 (InHIBIT-Bleed)46, Dupuis-Girod et al, 202360, Albitar et al, 202061, Al-Samkari et al, 202062, Al-Samkari et al, 201963 Iyer et al, 201841 | Largest published study to date (InHIBIT-Bleed) included 238 patients with HHT (observational study); no adequately powered prospective trial has yet been completed, although phase 2 NIH-sponsored TRUST-HHT study (ClinicalTrials.gov identifier: NCT04404881, anticipated recruitment 33 patients) is ongoing Data demonstrate significant and impactful improvements in hemoglobin, iron infusion requirements, red cell transfusion requirements, and ESS Most common adverse events in patients with HHT include hypertension (18%), fatigue (10%), and proteinuria (9%); venous thromboembolism observed in ∼10% of patients with metastatic cancer receiving bevacizumab with cytotoxic chemotherapy, vs 2% in patients with HHT (in InHIBIT-Bleed study), a number similar to the pomalidomide and placebo arms of the PATH-HHT RCT |
| Salvage systemic therapies (agents with limited evidence for safety and effectiveness) | ||||
| Pazopanib | Antiangiogenic and small-molecule VEGF receptor tyrosine kinase inhibitor | Oral | Parambil et al, 202164 Faughnan et al, 201965 | Largest published study to date included 13 patients with HHT (observational study); no adequately powered prospective trial has yet been completed, although US Department of Defense–sponsored phase 2/3 study (ClinicalTrials.gov identifier: NCT03850964, anticipated recruitment 70 patients) is ongoing Currently has breakthrough designation from US FDA for treatment of bleeding in HHT Limited data suggest significant improvements in hemoglobin, iron infusion requirements, red cell transfusion requirements, and ESS Limited data suggest common side effects in patients with HHT include hypertension, lymphocytopenia, and fatigue Data too limited to evaluate thromboembolic risk in HHT |
| Thalidomide | Antiangiogenic, immunomodulatory imide drug that suppresses production of VEGF-A, basic fibroblast growth factor, angiopoietins, and other angiogenic growth factors,56,57 and improves vessel wall integrity in telangiectasias58 | Oral | Invernizzi et al, 201547, Hosman et al, 201548, Baysal et al, 201949 Fang et al, 201750 | Largest published study to date included 31 patients with HHT (prospective) Limited data suggest significant improvements in epistaxis severity, hemoglobin, and red cell transfusion requirements Most common adverse events in patients with HHT include constipation (71%), drowsiness (21%), and elevation of thyroid-stimulating hormone (18%) Data too limited to evaluate thromboembolic risk in HHT, although in patients with multiple myeloma, clinical trials have demonstrated a much higher thromboembolic risk with thalidomide than pomalidomide Peripheral neuropathy, which may be irreversible, is common with thalidomide treatment (and very rare with pomalidomide treatment). The risk of peripheral neuropathy increases with ongoing duration of thalidomide exposure; up to ∼15% of patients with HHT developed peripheral neuropathy within the first 6 months of thalidomide treatment in a prospective clinical trial. |
| Octreotide, lanreotide | Somatostatin analogs that reduce splanchnic blood flow, slowing chronic gastrointestinal bleeding | Subcutaneous Intramuscular IV (emergent situations) | Torres-Iglesias et al, 202366 Kroon et al, 201967 | Largest published study to date included 67 patients with HHT (observational) No impact on epistaxis Limited data suggest significant improvements in hemoglobin and red cell transfusion requirements in patients with gastrointestinal bleeding Data too limited to evaluate adverse events in HHT, but largest published study reported diarrhea and/or abdominal pain in 24%, and discontinuation of treatment because of adverse events in 18% |
| Other notable systemic agents (novel/investigational and repurposed) | ||||
| Tacrolimus | Immunosuppressant, may potentiate the ALK1 pathway68 and possibly stimulate endoglin and ALK1 expression by endothelial cells69 | Oral | Hessels et al, 202270 | Largest published study to date included 25 patients with HHT (prospective); phase 2 study (ClinicalTrials.gov identifier: NCT04646356, anticipated recruitment 30 patients) in HHT, currently ongoing Limited data suggest significant improvements in ESS, hemoglobin, and red cell transfusion requirements Most common adverse events in patients with HHT include headache (40%), abdominal pain (32%), and diarrhea (32%) |
| Sirolimus | Immunosuppressant, inhibitor of mTOR, which is downstream of PI3K and AKT, potentially correcting overactivation of VEGFR271 | Oral | No study in HHT∗ published to date | Pilot study (ClinicalTrials.gov identifier: NCT05269849, anticipated recruitment 10 patients) in HHT, ongoing |
| VAD044 | Antiangiogenic, small-molecule allosteric inhibitor of AKT1, which is critical in vascular development and endothelial cell homeostasis72 | Oral | Investigational, no study published to date | Phase 1b VAD044002 study (ClinicalTrials.gov identifier: NCT05406362, anticipated recruitment 80 patients) in HHT, currently ongoing |
| Nintedanib | Antiangiogenic, small-molecule VEGF receptor tyrosine kinase inhibitor | Oral | No study in HHT∗ published to date | Two phase 2 studies (ClinicalTrials.gov identifier: NCT03954782, anticipated recruitment 30 patients and NCT04976036, anticipated recruitment 48 patients) in HHT, currently ongoing |
| Systemic agents not recommended for use | ||||
| Estrogens/ SERMs (tamoxifen, raloxifene, bazedoxifene) | Estrogenic compounds that increase circulating levels of procoagulant factors and improve vascular integrity73 | Oral IV (emergent situations) | Vase, 198174, van Cutsem et al, 199075, Yaniv et al, 200976 Yaniv et al, 201177 | Small studies, mixed results; negative RCT of systemic estrogen, RCT of tamoxifen with mixed results (reductions in visible blood and blood clots on nasal endoscopy but no improvement in hemoglobin); minimal data on other SERMs Feminizing effects (eg, gynecomastia) in male patients Known, well-defined increase in thromboembolic risk that is synergistic with other venous thromboembolic risk factors; risk of breast and/or uterine cancers given requirement for prolonged use Given the aforementioned, not recommended for use to treat bleeding in the most updated version of the International HHT Guidelines |
| Doxycycline | Tetracycline antibiotic with matrix metalloproteinase inhibitory effects,78 theorized to potentially have antiangiogenic properties | Oral | McWilliams et al, 202279 Faughnan et al, 202380 | Two RCTs with unambiguously negative results; no significant improvement in ESS, hemoglobin, hematologic support requirements, or any other primary or secondary end point in either trial Therefore, no indication for use to treat bleeding in HHT |
Most common adverse events are given for the largest published study of that agent in patients with HHT.
ALK1, activin-like receptor kinase 1; AKT, Ak strain transforming; mTOR, mammalian target of rapamycin; NIH, National Institutes of Health; PI3K, phosphoinositide-3-kinase; RCT, randomized controlled trial; SERM, selective estrogen response modifier; VEGFR2, vascular endothelial growth factor receptor 2.
Not including case reports.