Relative and absolute contraindications for use of primary systemic therapies in patients with HHT
| Agent . | Relative contraindications . | Absolute contraindications . |
|---|---|---|
| Antifibrinolytic agents (TXA and EACA) | Acute venous or arterial thromboembolism∗, Baseline severe renal impairment (TXA, requires careful dose modification) Acute subarachnoid hemorrhage Epilepsy (TXA) Active conjunctivitis Active hematuria Active myopathy (EACA)†, Bradycardia (IV EACA) Known severe thrombophilia with multiple prior unprovoked venous or arterial thromboembolic episodes‡ | Known allergy or hypersensitivity reaction to TXA or EACA Use of IV EACA formulations containing benzyl alcohol in neonates |
| Pomalidomide | Severe chronic constipation or irritable bowel syndrome Preexisting mild neutropenia (ANC < 1.5 × 109/L) Concomitant use of medications resulting in drowsiness or heavy alcohol consumption | Age <18 y Unwillingness or inability to comply with risk mitigation programs§, Preexisting moderate-to-severe neutropenia (ANC < 1.0 × 109/L) or thrombocytopenia (platelet count <50 × 109/L) Baseline severe renal impairment (estimated GFR <30 mL/min) Known allergy or hypersensitivity reaction to thalidomide, lenalidomide, or pomalidomide Drug-drug interactions resulting in inability to safely administer pomalidomide Known severe thrombophilia with multiple prior unprovoked venous or arterial thromboembolic episodes‡ Pregnancy Breastfeeding |
| Bevacizumab | Baseline uncontrolled mild-to-moderate hypertension||, Baseline proteinuria of ≥1000 mg protein per 24 h Baseline severe renal impairment (estimated GFR < 30 mL/min) Moderate-to-severe heart failure with reduced ejection fraction¶, Active skin or soft tissue infection Concomitant treatment with bisphosphonates (eg, zoledronic acid) or other antiresorptive agents (eg, denosumab)#, Known severe thrombophilia with multiple prior unprovoked venous or arterial thromboembolic episodes‡ Concomitant treatment with sunitinib or anthracyclines | Age <18 y Nephrotic syndrome Severe, uncontrolled hypertension (baseline pretreatment blood pressure >160/100 mm Hg)|| Active skin or soft tissue ulceration Recent major surgery (within 2-4 weeks) Active pulmonary hemorrhage Prior bowel perforation while receiving bevacizumab Known allergy or hypersensitivity reaction to bevacizumab Pregnancy Breastfeeding |
| Agent . | Relative contraindications . | Absolute contraindications . |
|---|---|---|
| Antifibrinolytic agents (TXA and EACA) | Acute venous or arterial thromboembolism∗, Baseline severe renal impairment (TXA, requires careful dose modification) Acute subarachnoid hemorrhage Epilepsy (TXA) Active conjunctivitis Active hematuria Active myopathy (EACA)†, Bradycardia (IV EACA) Known severe thrombophilia with multiple prior unprovoked venous or arterial thromboembolic episodes‡ | Known allergy or hypersensitivity reaction to TXA or EACA Use of IV EACA formulations containing benzyl alcohol in neonates |
| Pomalidomide | Severe chronic constipation or irritable bowel syndrome Preexisting mild neutropenia (ANC < 1.5 × 109/L) Concomitant use of medications resulting in drowsiness or heavy alcohol consumption | Age <18 y Unwillingness or inability to comply with risk mitigation programs§, Preexisting moderate-to-severe neutropenia (ANC < 1.0 × 109/L) or thrombocytopenia (platelet count <50 × 109/L) Baseline severe renal impairment (estimated GFR <30 mL/min) Known allergy or hypersensitivity reaction to thalidomide, lenalidomide, or pomalidomide Drug-drug interactions resulting in inability to safely administer pomalidomide Known severe thrombophilia with multiple prior unprovoked venous or arterial thromboembolic episodes‡ Pregnancy Breastfeeding |
| Bevacizumab | Baseline uncontrolled mild-to-moderate hypertension||, Baseline proteinuria of ≥1000 mg protein per 24 h Baseline severe renal impairment (estimated GFR < 30 mL/min) Moderate-to-severe heart failure with reduced ejection fraction¶, Active skin or soft tissue infection Concomitant treatment with bisphosphonates (eg, zoledronic acid) or other antiresorptive agents (eg, denosumab)#, Known severe thrombophilia with multiple prior unprovoked venous or arterial thromboembolic episodes‡ Concomitant treatment with sunitinib or anthracyclines | Age <18 y Nephrotic syndrome Severe, uncontrolled hypertension (baseline pretreatment blood pressure >160/100 mm Hg)|| Active skin or soft tissue ulceration Recent major surgery (within 2-4 weeks) Active pulmonary hemorrhage Prior bowel perforation while receiving bevacizumab Known allergy or hypersensitivity reaction to bevacizumab Pregnancy Breastfeeding |
ANC, absolute neutrophil count; GFR, glomerular filtration rate; EACA, ε-aminocaproic acid; TXA, tranexamic acid.
Requires clinical judgment; if on long-term antifibrinolytic therapy and thromboembolism appears unrelated, reasonable to continue effective antifibrinolytic treatment.
If using EACA in patients with known myopathy or skeletal muscle pathology, monitor creatine phosphokinase and discontinue if creatine phosphokinase rises.
This does not include paradoxical strokes through pulmonary AVMs, which is common in HHT, if the pulmonary AVMs have been adequately embolized. A prior history of severe thrombophilia and multiple thromboembolic events can be considered mitigated whether the patient is on anticoagulation and continues anticoagulation during the course of antiangiogenic or antifibrinolytic therapy.
Use of pomalidomide requires strict risk mitigation measures to ensure no potential exposure of pregnant females to the medication. This includes use of 2 highly-effective birth control methods in females of childbearing potential receiving pomalidomide (and for 4 weeks after discontinuation) as well as regular pregnancy tests (every 4 weeks if menses are regular, and every 2 weeks if they are not); avoidance of sharing pills with others and of blood or sperm donation while receiving treatment and for 4 weeks after discontinuation; and use of condoms in males taking pomalidomide if they are engaged in sexual intercourse with a female of childbearing potential.
Hypertension that is controlled with medications is not a contraindication to bevacizumab. Blood pressure should be controlled before initiation of bevacizumab.
Heart failure with preserved ejection fraction is not a contraindication. High-output cardiac failure is common in HHT and is not a contraindication to antiangiogenic therapy.
Concomitant administration of antiresorptive medications (in particular bisphosphonates) and bevacizumab may increase risk for osteonecrosis of the jaw.