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InHIBIT-Bleed: bevacizumab for bleeding in HHT
current HHT-directed therapies were compared to those in patients who did not receive concurrent HHT-directed therapies.
Safety analysis
Treatment-emergent adverse events (TEAE) were defined according to Common Terminology Criteria for Adverse Events v. 5.0 (National Cancer Institute) and recorded. To evaluate any impact of longer-term treatment on TEAE incidence, the number of TEAE per patient in those treated for 2 years or longer was compared with the number of TEAE per patient in those treated for less than 2 years.
Statistical analysis
Baseline hemoglobin concentration and ESS were compared with on-treatment mean values using the paired t-test. Pretreatment RBC transfusion and iron infusion requirements were compared with on-treatment values using the Wilcoxon signed-rank test. To estimate the change in each outcome meas- ure over time on treatment utilizing a method robust in the set- ting of missing data, a mixed effects linear model with a random intercept was also used for each outcome measure. Additional details regarding statistics, including analysis of subgroups, are detailed in the Online Supplementary Methods.
Results
Patients’ characteristics
Two hundred fifty-seven HHT patients were treated with systemic bevacizumab for epistaxis, gastrointestinal bleeding, or both for the purpose of alleviating bleeding and consequent iron-deficiency anemia at the 12 partici- pating centers during the study period. After 19 patients had been excluded because of inadequate chart data (missing baseline data or incomplete bevacizumab dosing information), 238 patients were included in the data analysis. Table 1 lists the patients’ baseline characteristics. Patients were treated for a median of 12 (range, 1-96) months, receiving a median of 11 (range, 1-74) infusions of intravenous bevacizumab. This totaled 343.9 patient- years of systemic bevacizumab treatment of HHT-associ- ated bleeding in the cohort.
Bevacizumab induction and maintenance dosing
Specific dosing protocols were institution-dependent. Two hundred twenty-one patients (93%) began treat- ment by receiving four to six induction infusions of beva- cizumab 5 mg/kg administered every 2 weeks; 46 (19%)
Table 1. Baseline characteristics of 238 patients with hereditary hemorrhagic telangiectasia treated with bevacizumab for chronic bleeding and iron deficiency anemia.
Characteristic
Age (years), mean (range)
% Female %DefiniteHHTbyCurac¸aocriteriaa Genetic mutation (HHT subtype)a
Baseline GI AVM and prior treatments
Baseline comorbidities relevant to bevacizumab treatment
Primary bleeding source
Mean baseline hemoglobin (95% CI)
Mean baseline epistaxis severity score (95% CI)
Prior local hemostatic treatments for epistaxis
Prior nasal septum perforation (%)
Value
63 (29-91)
62 97
ENG (HHT-1): 52 (22%)
ACVRL1 (HHT-2): 92 (39%)
SMAD4 (HHT-JPS): 4 (2%)
Other pathogenic HHT mutation: 6 (3%) Mutation not identified: 4 (2%)
Genetic testing not done: 80 (34%)
Known upper GI AVM: 148 (62%)
Known lower GI AVM: 47 (20%)
Received local endoscopic hemostatic treatments: 119 (50%)
Hypertension: 67 (29%)
Chronic kidney disease: 14 (6%) Diabetes mellitus: 20 (9%)
High-output heart failure: 32 (14%)
Prior venous thromboembolism: 27 (11%)
Epistaxis: 99 (42%)
GI bleeding: 46 (19%)
Both epistaxis and GI bleeding: 93 (39%)
Treated for anemia (baseline Hb <11) (N=197): 8.6 g/dL (8.4, 8.8)
All patients (N=232): 9.1 g/dL (8.9, 9.4)
Treated for epistaxis (N=175): 6.75 (6.52, 6.99) All patients (N=213): 5.92 (5.60, 6.24)
Any treatment: 182 (77%)
Laser cautery: 118 (50%)
Electrical or chemical cautery: 112 (47%) Nasal septodermoplasty: 38 (16%)
Nasal sclerotherapy: 58 (24%)
Nasal embolization: 21 (9%)
Bevacizumab nasal spray: 26 (10%)
Septal bevacizumab injection: 23 (9%) Nasal closure (Young’s procedure): 9 (4%)
32 (13%)
aThe Curac¸ao criteria are used to establish the diagnosis of hereditary hemorrhagic telengiectasia (HHT); the presence of three or four out of four criteria denotes “definite HHT”, while the presence of two out of four criteria signifies “possible HHT”. Genetic testing is not required for a diagnosis of HHT but is done to identify HHT subtype. 95% CI: 95% confidence interval;GI,gastrointestinal.AVM,arteriovenous malformation.JPS,juvenile polyposis syndrome.
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