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InHIBIT-Bleed: bevacizumab for bleeding in HHT
cizumab. There were no fatal TEAE. The TEAE rate was slightly higher in patients receiving intermittent mainte- nance (51%) than in those receiving continuous mainte- nance (32%). There was no significant difference in number of reported TEAE in patients with long-term exposure to bevacizumab (≥2 years) and those with shorter-term expo- sure (<2 years) with a mean of 0.57 versus 0.53 TEAE per patient, respectively (P=0.80, Mann-Whitney U test).
The rate of VTE in HHT patients receiving bevacizumab was 1.5 events per 100 patient-years at risk. Online Supplementary Table S6 shows the venous thromboembolic events occurring in the cohort of patients.
Bevacizumab discontinuation
Twelve patients (5%) discontinued bevacizumab treat- ment because of adverse events. Online Supplementary Table S7 describes the adverse events prompting treatment dis- continuation. Eleven patients (5%) discontinued beva- cizumab because of inadequate treatment effect. Discontinuation due to excessive financial cost for patients occurred in two cases (1%).
Discussion
We present a large, international, multicenter study of systemic bevacizumab treatment of HHT-associated bleed- ing, observing striking improvements in bleeding and ane- mia with bevacizumab treatment (Figure 1, Online Supplementary Figure S1). Historically, reports on beva- cizumab treatment for HHT-related bleeding have been limited to single case reports and small cohorts from indi- vidual treatment centers. Before the present study, the largest study of systemic bevacizumab for bleeding and anemia in HHT, evaluating critical hematologic outcomes such as hemoglobin, blood transfusion and iron infusion, was a 13-patient case series.23
Table 3. Treatment-emergent adverse events (TEAE) identified by treat- ing clinicians as likely or possibly due to bevacizumab. TEAE were evaluable in 232 patients.
We found that bevacizumab was effective at reducing HHT-associated bleeding regardless of the patients’ geno- type, with an improvement in mean hemoglobin of 3.2 g/dL and resolution of anemia in two-thirds of patients. The severity of epistaxis also declined sharply, with a drop in mean ESS of 3.37 points, nearly five times the minimal clin- ically-important difference of 0.71 for this well-validated clinical bleeding score.29 Concurrent with the improve- ments in hemoglobin, RBC transfusions and iron infusions dropped precipitously: 80% and 61% of patients previously requiring RBC transfusions and iron infusions, respectively, were liberated entirely from these hematologic support modalities after 6 months of treatment. Improvement was observed irrespective of baseline bleeding or anemia sever- ity and included the most severely afflicted patients (Figure 2). Similar improvement was observed regardless of the underlying pathogenic mutation (Online Supplementary Table S3). Most patients did not receive any additional concurrent treatments to manage HHT-associated bleeding once on bevacizumab, and outcomes of the patients who did were actually slightly worse than those who did not (Online Supplementary Table S5). This is likely reflective of less improvement with bevacizumab in these patients prompt- ing the need for additional therapies. The fact that patients not receiving any other bleeding-directed treatments had such significant improvement in hematologic parameters with bevacizumab initiation increases our confidence in the relationship between bevacizumab treatment and the dra- matic improvement observed in these parameters.
The effectiveness observed with systemic bevacizumab treatment in this study is considerably better than that found for other systemic agents evaluated for HHT-associ- ated bleeding.30 Small randomized studies of tranexamic acid versus placebo suggest mild to moderate improvements in epistaxis severity but no improvement in hemoglobin with the active treatment.12,31 A small randomized study of oral estrogen compared with placebo found no significant improvement in epistaxis.32 Topical nasal pharmacotherapy has been similarly disappointing, with randomized studies of topical timolol, estrogen, and tranexamic acid all show- ing no difference in the comparison with placebo.33,34 Bevacizumab via topical nasal spray has also been evaluat- ed, with no improvement noted in epistaxis severity in the comparison with placebo.33,35 Therefore, given the lack of other effective options and the continued lack of any Food and Drug Administration-approved treatment, our findings suggest it may be appropriate to consider systemic beva- cizumab in patients with moderate-to-severe HHT-associ- ated bleeding (Online Supplementary Table S1) without con- traindications. This may be particularly true for patients with significant gastrointestinal bleeding, who constituted over half the cohort in the present study, for whom there are no studies of other pharmacological interventions. Oral anti-angiogenics such as pomalidomide36 and pazopanib37,38 are additionally under investigation for treatment of HHT- associated bleeding. Should these agents demonstrate effi- cacy, head-to-head studies comparing them with beva- cizumab will be needed.
While initial bevacizumab induction treatment schedules were quite similar between different centers, maintenance strategies varied considerably, with some centers employ- ing continuous scheduled maintenance and others opting for an intermittent, as-needed approach to minimize overall bevacizumab exposure. Both approaches were effective, but intermittent maintenance (which employed 75% of the
TEAE
Hypertension (new-onset or worse from baseline)
Fatigue
Proteinuria
Myalgia and/or arthralgia
Headache
Venous thromboembolism
Transaminase/alkaline phosphatase elevation
Rash
Abdominal pain/gastrointestinal upset
Lightheadedness
Dyspnea
Hoarseness
Bone marrow suppression
Otherc
Number of patients (%)
41 (18%)a
23 (10%) 21 (9%)b 14 (6%) 9 (4%)
5 (2%)
3 (1%)
3 (1%)
3 (1%)
2 (1%)
2 (1%)
2 (1%)
2 (1%)
7 (3%)
a26 patients with new-onset hypertension and 15 patients with hypertension worsened from baseline; bOccurred in one patient with baseline chronic kidney disease and three patients with baseline diabetes mellitus. cIncludes one report each of lower extremity edema,worsened epistaxis,diarrhea,lower extremity venous ulceration,poor wound healing, non-cardioembolic stroke, and Staphylococcus aureus skin infection.
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