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© 2016 American Medical Association. All rights reserved.
Supplementary Online Content
Whitehead KJ, Sautter NB, McWilliams JP, et al. Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia: a randomized clinical trial. JAMA. doi:10.1001/jama.2016.11724
List of Investigators
eMethods
eText. Epistaxis Severity Score (ESS) for HHT questionnaire
eFigure. Descriptive profile of epistaxis frequency and duration over time.
eTable 1. Individual components of the Epistaxis Severity Score
eTable 2. Adverse Events
eReferences
This supplementary material has been provided by the authors to give readers additional information about their work.
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List of Investigators
Organizing Committee: Clancy MS, Faughnan ME, Gossage JR, Letarte M, Oh SP,
Olitsky SE, Pyeritz RE, Sprecher D. Statistician: Johnson MH. Main writing
committee: Gossage JR, Johnson MH, Whitehead KJ. Data Safety Monitoring Board:
Davidson TM *, Hoag JB, Kutlar A, Layman LC, Piccirillo, JF. Data extraction:
Johnson KW, Lee T, Lundeen JS. Enrolling Centers: University of Utah - Whitehead KJ
(site PI), McDonald J, Neuharth RM, Ward PD, Wilson KF; Augusta University -
Gossage JR (site PI), James M, Johnson MH, Whitehouse A; Oregon Health and Sciences
University - Sautter NB (site PI), Chesnutt MS, Farrar CA, French M; University of
California Los Angeles - McWilliams JP (site PI), Duckwiler GR, Kay PA, Quinn B, Suh
RD, Wang MB; Washington University - Chakinala MM (site PI), Dornseif S, Duncan
M, Heuerman SL, Piccirillo JF; Johns Hopkins University - Merlo CA (site PI), Mitchell
SE, Reh DD, Robinson GM.
* Deceased March 2013
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eMethods
OUTCOMES AND ASSESSMENTS
The Epistaxis Severity Score (ESS) is derived from 6 questions about epistaxis
frequency, epistaxis duration, epistaxis intensity, presence of anemia, need for blood
transfusion, and need to seek medical care1. For this study the ESS at all time points was
based on the patient’s epistaxis during the prior 4 weeks. It has a range of 0-10 where 0-
3.99 is mild, 4-6.99 is moderate, and 7-10 is severe. The minimal important difference
(MID) has been determined to be 0.41 via the anchor-based approach and 1.01 via the
distribution-based approach, giving a mean MID of 0.712. The decision to have blood
transfusion, visit the emergency room, or seek any other type of care was at the discretion
of the patient and investigator. However, in practice HHT patients do not usually receive
transfusion unless the hemoglobin drops below 7-8 gm/dl.
Baseline assessments included: a history and physical examination; patient
estimate of the number of epistaxis episodes per week during the 4 weeks prior to
baseline; ESS; and phlebotomy for hemoglobin and ferritin. Each patient was contacted
by phone at 1, 2, 4, and 8 weeks to monitor for side effects and to encourage compliance
with epistaxis diary completion and drug use. Adverse events were reported and any new
symptoms not present at baseline or worsening from baseline were tracked. Patients
returned at 12 weeks to repeat the baseline assessments and return study drug. Patients
were contacted by phone at 24 weeks to repeat the ESS and return the diary for weeks 13-
24.
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eText. Epistaxis Severity Score (ESS) For HHT (Version 06/07/11)
The purpose of these questions is to calculate a severity score of epistaxis (nose bleeding) for patients with Hereditary Hemorrhagic Telangiectasia who are taking part in the HHT NOSE study. Please answer each of the following questions as they pertain to your TYPICAL (usual or most common) symptoms during the past 4 weeks.
1. How often did you TYPICALLY have nose bleeding during the past 4 weeks? Less than monthly [0] Once per month [1] Once per week [2] Several per week [3] Once per day [4] Several per day [5]
2. How long did your nose bleeding episodes TYPICALLY last during the past 4weeks?
Less than 1 minute [0] 1 to 5 minutes [1] 6 to 15 minutes [2] 16 to 30 minutes [3] More than 30 minutes [4]
3. How would you describe your TYPICAL nose bleeding intensity during the past 4weeks?
Not Typically Gushing or Pouring [0] Typically Gushing or Pouring [1]
4. Have you sought medical attention for your nose bleeding during the past 4weeks?
No [0] Yes [1]
5. Are you anemic (low blood counts) currently? No [0] Yes [1] I don’t know [2]
6. Have you received a red blood cell transfusion SPECIFICALLY for nosebleeding during the past 4 weeks?
No [0] Yes [1]
This is the form used to document and calculate the ESS. The bracketed numbers in blue after each response show how data were documented and analyzed for eTable 1 (these numbers were not present on the actual form that the patient would fill out). For example, most patients answered option 3, 4, or 5 for Question 1. As a result, the means for Question 1 averaged around 4.
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The calculation of ESS was performed according to the algorithm defined by Hoag et al. (Laryngoscope 120:838-843, 20101) and can also be found online at: https://www2.drexelmed.edu/HHT-ESS/
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eFigure. Descriptive profile of epistaxis frequency and duration over time
(A) Epistaxis frequency reported as a weekly median value taken from the nosebleed diary. Active treatment was provided from baseline to week 12. The pre-specified analysis phase for the primary outcome is shaded in gray from week 5 to week 12. There was considerable variation in epistaxis frequency (data reported as median number of bleeds, IQR). No drug effects were seen. Between weeks 5 and 12 the following were observed: bevacizumab (7.0, 4.5-10.5), estriol (8.0, 4.0-12.0), tranexamic acid (7.5, 3.0-11.0), placebo (8.0, 3.0-14.0). An observation phase continued for weeks 13-24. The values for median (B) epistaxis duration per bleed were also derived from the nosebleed diary. The analysis phase for the secondary outcome is shaded in gray from week 5 to week 12. No drug effects were seen. Between weeks 5 and 12 the following were observed (median minutes of bleeding, IQR): bevacizumab (3.0, 1.6-5.5), estriol (4.0,
1.6-6.3), tranexamic acid (6.2, 3.0-9.4), placebo (5.0, 3.0-9.8).
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eTable 1. Individual components of the Epistaxis Severity Score
Bevacizumab Estriol Tranexamic
acid Placebo
Patients, N
Baseline 29 30 33 28
Week 12 25 24 32 24
Week 24 22 16 24 21
Question 1 (Frequency) Range 0 to 5
Baseline 4.28
(3.99, 4.56) 4.10
(3.70, 4.50) 4.30
(4.02, 4.59) 4.32
(4.00, 4.64)
Week 12 4.00
(3.55, 4.45) 3.67
(3.13, 4.20) 3.72
(3.25, 4.19) 3.67
(3.09, 4.25)
Week 24 3.91
(3.44, 4.38) 3.56
(2.98, 4.15) 3.75
(3.26, 4.24) 4.05
(3.48, 4.61) Question 2 (Duration) Range 0 to 4
Baseline 1.69
(1.37, 2.01) 1.90
(1.52, 2.28) 1.76
(1.56, 1.96) 2.11
(1.75, 2.46)
Week 12 1.08
(0.74, 1,42) 1.29
(0.91, 1.68) 1.50
(1.24, 1.76) 1.63
(1.32, 1.93)
Week 24 1.41
(1.03, 1.79) 1.50
(0.85, 2.15) 1.63
(1.26,1.99) 1.67
(1.25, 2.08) Question 3 (Intensity) Range 0 to 1
Baseline 0.45
(0.26, 0.64) 0.27
(0.10, 0.43) 0.36
(0.17, 0.56) 0.46
(0.27, 0.66)
Week 12 0.16
(0.01, 0.31) 0.25
(0.03, 0.47) 0.09
(0, 0.23) 0.17
(0.01, 0.33)
Week 24 0.27
(0.07, 0.47) 0.31
(0.06, 0.57) 0.21
(0.03, 0.38) 0.29
(0.08, 0.50) Question 4 (Medical attention) Range 0 to 1
Baseline 0.59
(0.40, 0.78) 0.67
(0.49, 0.85) 0.61
(0.43,0.78) 0.64
(0.45, 0.83)
Week 12 0
(-, -) 0
(-, -) 0.13
(0, 0.25) 0
(-, -)
Week 24 0.14
(0, 0.29) 0.19
(0, 0.40) 0.17
(0.01, 0.33) 0.05
(0, 0.15)
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Question 5 (Anemia) Range 0 to 2
Baseline 0.61
(0.39, 0.83) 0.57
(0.33, 0.80) 0.79
(0.56, 1.02) 0.50
(0.28, 0.72)
Week 12 0.68
(0.40, 0.96) 0.42
(0.14, 0.69) 0.88
(0.62, 1.13) 0.38
(0.13, 0.62)
Week 24 0.55
(0.22, 0.87) 0.56
(0.13, 1.00) 1.21
(0.90, 1.51) 0.43
(0.12, 0.74) Question 6 (Tranfusion) Range 0 to 1
Baseline 0.03
(0, 0.11) 0.03
(0, 0.10) 0.12
(0, 0.24) 0.14
(0, 0.28)
Week 12 0
(-, -) 0.04
(0, 0.13) 0.06
(0, 0.15) 0
(-, -)
Week 24 0
(-, -) 0
(-, -) 0.13
(0, 0.27) 0.05
(0, 0.15) ESS Range 0 to 10
Baseline 5.16
(4.75, 5.57) 5.19
(4.71, 5.68) 5.43
(4.94, 5.91) 5.71
(5.04, 6.38)
Week 12 3.54
(3.00, 4.08) 3.56
(2.81,4.30) 4.06
(3.50, 4.61) 3.74
(3.17, 4.31)
Week 24 3.88
(3.28, 4.47) 3.83
(2.61, 5.04) 4.40
(3.67, 5.12) 4.26
(3.65, 4.88) The mean (95% CI) responses to each of the six individual components of the Epistaxis
Severity Score (ESS) at baseline, week 12, and week 24 are shown above. The specific
questions with corresponding scoring for possible responses are outlined in the “Epistaxis
Severity Score (ESS) for HHT questionnaire” on page 6 of this supplement.
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eTable 2. Adverse Events
Bevacizumab Estriol Tranexamic
acid Placebo
n/total n (%) n/total n (%) n/total n (%) n/total n (%)
Gastrointestinal
Nausea or vomiting § ¶ 4/29 (14) 1/30 (3) 10/33 (30) 8/28 (29)
Diarrhea 4/29 (14) 3/30 (10) 9/33 (27) 2/28 (7)
Abdominal pain § ‡ 5/29 (17) 2/30 (7) 10/33 (30) 1/28 (4)
Diverticulitis flare 0/29 (0) 1/30 (3) 0/33 (0) 0/29 (0)
Heart Burn/Indigestion 1/29 (3) 0/30 (0) 0/33 (0) 1/28 (4)
Loss of appetite 0/29 (0) 0/30 (0) 1/33 (3) 0/28 (0)
Any GI ∞ 6/29 (21) 4/30 (13) 17/33 (52) 10/28 (36)
Gynecologic
Breast pain/swelling 2/29 (7) 2/30 (7) 4/33 (12) 1/28 (4)
Hot Flash 3/29 (10) 4/30 (13) 3/33 (9) 3/29 (11)
PMS* 0/13 (0) 0/12 (0) 0/14 (0) 1/13 (8)
Amenorrhea* 0/13 (0) 0/12 (0) 1/14 (7) 1/13 (8)
Vaginal discharge* 1/13 (8) 0/12 (0) 0/14 (0) 0/13 (0)
Vaginal Bleed* 2/13 (15) 3/12 (25) 0/14 (0) 0/13 (0)
ENT
Nasal symptoms 11/29 (38) 12/30 (40) 10/33 (30) 10/28 (36)
Increased nosebleeds 2/29 (7) 2/30 (7) 1/33 (3) 0/28 (0)
Cardiopulmonary
Cough 4/29 (14) 2/30 (7) 8/33 (24) 4/28 (14)
Leg edema 2/29 (7) 0/30 (0) 2/33 (6) 2/28 (7)
Chest pain 0/29 (0) 1/30 (3) 2/33 (6) 2/28 (7)
Heart Murmur 1/29 (3) 0/30 (0) 0/33 (0) 0/28 (0)
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Musculoskeletal
Musculoskeletal pain 3/29 (10) 5/30 (17) 5/33 (15) 4/28 (14)
Heel spur 1/29 (3) 0/30 (0) 0/33 (0) 0/28 (0)
Gout Flare 0/29 (0) 1/30 (3) 0/33 (0) 0/28 (0)
Bleeding
Intestinal Bleeding 1/29 (3) 2/30 (7) 1/33 (3) 1/28 (4)
Lung Bleeding 0/29 (0) 0/30 (0) 0/33 (0) 1/28 (4)
Oral Bleeding 1/29 (3) 0/30 (0) 2/33 (6) 1/28 (4)
Infectious
Urinary tract infection 3/29 (10) 5/30 (17) 3/33 (9) 4/28 (14)
Bronchitis 1/29 (3) 0/30 (0) 1/33 (3) 0/28 (0)
Pneumonia 1/29 (3) 2/30 (7) 0/33 (0) 0/28 (0)
Flu 1/29 (3) 0/30 (0) 1/33 (3) 0/28 (0)
Sinusitis 0/29 (0) 1/30 (3) 1/33 (3) 0/28 (0)
Fever 0/29 (0) 1/30 (3) 0/33 (0) 0/28 (0)
Thrush 0/29 (0) 1/30 (3) 0/33 (0) 0/28 (0)
Miscellaneous Infection 1/29 (1) 2/30 (7) 1/33 (3) 0/28 (0)
Neurologic
Headache 10/29 (34) 12/30 (40) 10/33 (30) 6/28 (21)
Vision problem 2/29 (7) 2/30 (7) 5/33 (15) 1/28 (4)
Decreased memory 0/29 (0) 0/30 (0) 1/33 (3) 0/28 (0)
Feeling Down 0/29 (0) 0/30 (0) 1/33 (3) 0/28 (0)
Increased Dreams 0/29 (0) 0/30 (0) 1/33 (3) 0/28 (0)
Dizziness /lightheaded 1/29 (3) 0/30 (0) 3/33 (9) 2/28 (7)
Syncope 0/29 (0) 1/30 (3) 0/33 (0) 1/28 (4)
Anxiety 0/29 (0) 0/30 (0) 0/33 (0) 1/29 (4)
Weak 0/29 (0) 0/30 (0) 1/33 (3) 0/28 (0)
Twitching 0/29 (0) 1/30 (3) 1/33 (3) 0/28 (0)
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Cysts and nodules
Benign Thyroid Nodule 1/29 (3) 0/30 (0) 0/33 (0) 0/28 (0)
Skin cancer lesion 1/29 (3) 0/30 (0) 0/33 (0) 0/28 (0)
Uterine cyst* 1/13 (8) 0/12 (0) 0/14 (0) 0/13 (0)
Laboratory
Anemia 1/29 (3) 2/30 (7) 1/33 (3) 0/28 (0)
Increased pCO2 1/29 (3) 1/30 (3) 0/33 (0) 0/28 (0)
Vitam D deficiency 0/29 (0) 0/30 (0) 0/33 (0) 1/28 (4)
Increased WBC 0/29 (0) 1/30 (3) 0/33 (0) 0/28 (0)
Miscellaneous
Urinary retention 1/29 (3) 0/30 (0) 0/33 (0) 0/28 (0)
Dehydration 0/29 (0) 0/30 (0) 2/33 (6) 0/28 (0)
Elevated BP 0/29 (0) 0/30 (0) 0/33 (0) 1/28 (4)
General bloating 0/29 (0) 0/30 (0) 1/33 (3) 0/28 (0)
Itching 0/29 (0) 0/30 (0) 2/33 (6) 1/28 (4)
Altered taste 0/29 (0) 0/30 (0) 0/33 (0) 1/28 (4)
Tired 1/29 (3) 0/30 (0) 0/33 (0) 0/28 (0)
Acne 1/29 (3) 0/30 (0) 0/33 (0) 0/28 (0)
Increased hair loss 1/29 (3) 0/30 (0) 0/33 (0) 0/28 (0)
Eyes burning 0/29 (0) 0/30 (0) 1/33 (3) 0/28 (0)
Fluid on the ear 0/29 (0) 0/30 (0) 1/33 (3) 0/28 (0)
Any Adverse Event 24/29 (83) 25/30 (83) 26/33 (79) 23/28 (82)
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The complete list of adverse events reported by study participants, divided by organ system. The data reflect the number of patients experiencing an event, not the total number of events. § P < 0.05, Fisher’s Exact Test.¶ Tranexamic acid and placebo significantly greater than estriol after Bonferroni correction ‡ Tranexamic acid significantly greater than estriol and placebo after Bonferroni correction ∞ P < 0.01, Fisher’s Exact Test. Tranexamic acid significantly greater than estriol and bevacizumab after Bonferroni correction * The percentages for these events were calculated for females only (N = bevacizumab13, estriol 12, tranexamic acid 14, placebo 13).
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eReferences
1. HoagJB,TerryP,MitchellS,RehD,MerloCA.Anepistaxisseverityscoreforhereditaryhemorrhagictelangiectasia.Laryngoscope.2010;120(4):838‐843.
2. YinLX,RehDD,HoagJB,etal.Theminimalimportantdifferenceoftheepistaxisseverityscoreinhereditaryhemorrhagictelangiectasia.Laryngoscope.2016;126(5):1029‐1032.
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