Letters RESEARCH LETTER

Safety of Propranolol Therapy for Severe Infantile Hemangioma

Table 1. Demographic and Clinical Data at Inclusion of 906 Children Followed up in the French Compassionate Use Program for Propranolol No./Total (%) of Childrena

Infantile hemangioma is a vascular tumor characterized by rapid growth during the first weeks of life and spontaneous involution over a few years.1 Severe forms require systemic therapy. Propranolol induces regression, but safety data are lacking in children.2,3 Methods | The French Health Products Agency (ANSM) allows compassionate use of promising off-label drugs without available therapeutic alternatives. Children throughout France with proliferative infantile hemangioma requiring systemic therapy for life-threatening (ie, potential airway obstruction) or functional risks (ie, amblyopia) or severe ulceration were referred to specialist centers for compassionate use of pediatric oral propranolol.4 Analyses involved data collected between April 2010 and April 2013 of consecutive children enrolled during this period after ANSM institutional board approval and parents’ verbal consent. Demographic and clinical data were collected at inclusion. Adverse drug reactions (ADRs) were collected by questioning parents and reviewing the child health record at each monthly visit for up to 2 years. Causality was established by the pharmaceutical company providing propranolol using the standard method in France, confirmed by ANSM and the first author, and based on chronological, clinical, and pharmacological criteria on a scale from 0 (unlikely) to 5 (very likely) with 2 or greater considered possibly related to propranolol.5 Results | Of 922 patients referred, 906 were treated with propranolol and had a median age of 114 days (interquartile range [IQR], 1-2282 days; mean, 185 days). Indications for treatment included functional impairment in 72.4%, severe ulceration in 40.0%, and life-threatening conditions in 16.2% (Table 1). Before inclusion, 43 patients had received systemic therapies, mainly corticosteroids (n = 34). Propranolol was administered at a median dose of 2.0 mg/kg/d (IQR, 0.4-4.0 mg/kg/d) for a median duration of 198 days (IQR, 3-929 days). Median duration of follow-up was 396 days (IQR, 18-730 days). Of 313 children who stopped propranolol by April 2013, 83.7% stopped for satisfactory efficacy and 5.8% for ADRs. Of 922 patients, 81 (8.8%) had 133 ADRs, including 24 (2.6%) with 36 serious ADRs (Table 2). The most commonly reported ADRs were respiratory disorders (mostly infections), which were reported in 31 patients (serious ADRs related to propranolol in 6 patients). The most serious ADRs were cardiac and metabolic disorders. jama.com

Sex Male

226/902 (25.1)

Female

676/902 (74.9)

Age at inclusion, median (range), d ≤90

114 (1-2282)b 318/905 (35.1)

90-150

309/905 (34.1)

>150

278/905 (30.7)

Weight, median (range), kg Height, median (range), cm

5.8 (2.0-23.8)c 59.2 (34-121)d

Medical history Prematurity Bronchiolitis or bronchitis Asthma

210/905 (23.2) 26/693 (3.8) 5/904 (0.6)

Familial or personal history of atopy

140/879 (15.9)

Hemangioma localization Facial

584/906 (64.5)

Internal

82/888 (9.2)

Hemangioma gravity factor Severe ulceration

347/867 (40.0)

Functional impairment

634/876 (72.4)

Life-threatening conditions

138/854 (16.2)

a

Unless otherwise indicated.

b

There were 905 children with data available.

c

There were 900 children with data available.

d

There were 777 children with data available.

Four patients had cardiac ADRs, 2 of which were serious ADRs related to propranolol. One death occurred in a 5-month-old child with biliary atresia and portal hypertension, with satisfactory cardiac monitoring, after 14 days of propranolol treatment (dose: 2 mg/kg/d) for hemangioma. Fatal atrioventricular block occurred 15 minutes after sclerotherapy with lauromacrogol for esophageal varices. Causality with propranolol was considered doubtful. In the second case, bradycardia was detected on cardiac monitoring 9 days after initiation of propranolol in a 4-month-old child with metabolic disease; the holter electrocardiogram improved after discontinuation. Four patients experienced serious hypoglycemia, including 2 children aged 8 and 9 months with hypoglycemic seizures 5.5 and 7 months after propranolol introduction, respectively. One hypoglycemic seizure occurred due to viral gastroenteritis (after fasting and vomiting) and 1 after poor food intake; both recovered after glucose perfusion. (Reprinted) JAMA January 26, 2016 Volume 315, Number 4

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Tennessee - Knoxville User on 01/27/2016

413

414

There was 1 death.

There was 1 purpuric eruption, 1 breath-holding spell, 1 febrile urinary tract infection, and 1 fall after hitting a door (classified as an SADR due to hospitalization). f

Causality with propranolol was determined by the relationships of time to drug intake, effect of dechallenge or rechallenge of propranolol, absence of other disease or drugs explaining the ADR, and whether the ADR was a known adverse effect of propranolol. These relationships were assessed on a scale from 0 (unlikely causality) to

e

c

All 4 patients had hypoglycemia and 2 of the 4 experienced hypoglycemic seizures. d

An SADR was defined as any ADR leading to death, life-threatening injury, hospitalization (initial or prolonged), disability or permanent damage, or other important medical events as judged by the investigator. b

5 (very likely causality). Patients with a score of 2 or greater were considered to have an ADR possibly related to propranolol. An ADR was defined as any undesirable experience associated with the use of a medical product in a patient. Patients could have more than 1 ADR.

2/4 (50.0) 2 (1-2) 71 (4-187) 6 (1-14) 0 4 (16.7)f 0 11 (13.6) Other

a

2/4 (50.0)

11/11 (100)

1/3 (33.3) 2 (2-2) 9 (1-19) 4 (1-5) 2 (2.5) Cardiac

4 (4.9)e

3 (12.5)e

2 (8.3)

4/11 (36.3)

4/4 (100) 1/3 (33.3) 1.5 (1.0-3.0) 87 (0-218) 9 (5-15) 4 (4.9)d Metabolic

4 (4.9)d

4 (16.7)d

4 (16.7)d

3/4 (75.0)

9/9 (100) 0/3 2 (2-2) 71 (2-73) 4 (3-6) 3 (3.7) Digestive

9 (11.1)

1 (4.2)

1 (4.2)

3/4 (75.0)

9/9 (100) 3/3 (100) 2 (1-3) 5 (1-97) 7 (2-12) 6 (7.4) Vascular

9 (11.1)

2 (8.3)

2 (8.3)

3/9 (33.3)

12/17 (70.6) 2/5 (40.0)

3/9 (33.3)

31/31 (100) 10/25 (40.0)

2 (2-3) 49 (0-305) 7 (5-16)

5/20 (25.0)

2 (1-3) 90 (7-222) 8 (4-11) 6 (25.0)

7 (8.6)

10 (41.7) 9 (11.1)

20 (24.7) Sleep

Respiratory

31 (38.3)

All All

0

0

25/31 (80.6)

Resolution of ADR Successfully Restarted Propranolol Withdrew Propranolol Propranolol Dosage, mg/kg/d Time From Propranolol Initiation to ADR, d Age of Patients, mo

Median (Range)

Related to Propranololc Related to Propranololc Type of Organ System Disorder

No. (%) of Patients With an SADR (n = 24)b No. (%) of Patients With an ADR (n = 81)a

Table 2. Description of Adverse Drug Reactions (ADRs) and Serious ADRs (SADRs) Related to Propranolol Classified by Organ System Disorder

No./Total (%)

Letters

Other common ADRs included sleep disturbances, primarily nightmares (12/20 cases); benign vascular disorders (7 acrocyanosis and 2 asymptomatic hypotension); and digestive disorders, primarily benign diarrhea (5 cases). These ADRs often resolved when treatment administration was altered (ie, earlier evening dose or decreasing daily dose). Propranolol was stopped for 45/88 (51%) of patients and successfully restarted in 18 (40%). Discussion | This large prospective cohort study found that serious ADRs were rare when propranolol was used to treat severe infantile hemangiomas, confirming 2 smaller studies.3,6 The most serious ADR was bradycardia, which occurred in children with severe comorbidities despite monitoring at initiation. Also worrisome were bronchoreactivity and hypoglycemia, aggravated by the β-adrenergic antagonist properties of propranolol, and worsening conditions of children who also had other concomitant diseases. Limitations include that off-label prescription of propranolol could have been missed, and there was no control group. Attribution of causality may not be accurate, but the criteria used are well established. Prescribers must counsel parents at each follow-up visit to discontinue propranolol during fasting and intercurrent illness, especially in the setting of restricted oral intake and respiratory symptoms. Sorilla Prey, MD Jean-Jacques Voisard, MD Alain Delarue, MD Geneviève Lebbe, MD Alain Taïeb, MD, PhD Christine Leaute-Labreze, MD Khaled Ezzedine, MD, PhD Author Affiliations: Service de Dermatologie, CIC P 1401 et Inserm U1035-CHU et Université de Bordeaux, Bordeaux, France (Prey, Taïeb, Leaute-Labreze, Ezzedine); Laboratoire Pierre Fabre Dermatologie, Lavaur, France (Voisard, Delarue, Lebbe). Corresponding Author: Sorilla Prey, MD, Service de Dermatologie Pédiatrique et Centre de Référence des Maladies Rares de la Peau, Hôpital des Enfants Pellegrin, Place Amélie Raba Léon, 33 076 Bordeaux, France ([email protected]). Author Contributions: Dr Prey had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Leaute-Labreze and Ezzedine contributed equally to this work. Study concept and design: Prey, Voisard, Léauté-Labrèze. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Prey, Taïeb, Léauté-Labrèze, Ezzedine. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Prey, Ezzedine. Administrative, technical, or material support: Prey, Voisard, Delarue, Lebbe, Taïeb, Léauté-Labrèze. Study supervision: Prey, Voisard, Taïeb, Léauté-Labrèze, Ezzedine. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Prey and Leaute-Labreze reported being investigators in clinical trials evaluating propranolol in infantile hemangioma promoted by Pierre Fabre Dermatologie pharmaceutical company. No other disclosures were reported.

JAMA January 26, 2016 Volume 315, Number 4 (Reprinted)

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Tennessee - Knoxville User on 01/27/2016

jama.com

Letters

Funding/Support: This study was supported by Pierre Fabre Dermatologie pharmaceutical company and the French Health Products Agency. The pharmaceutical company developed and provided the oral pediatric specific formulation of propranolol chlorhydrate. Role of the Funder/Sponsor: Pierre Fabre Dermatologie pharmaceutical company and the French Health Products Agency had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We thank Valérie Ortis, MD (Laboratoire Pierre Fabre Dermatologie, Lavaur, France), for coordinating the French Compassionate Use Program, in particular checking inclusion criteria and collection of vigilance data, and Sarah Tilly, MS (Scinopsis, Frejus, France), for reviewing the manuscript. Both were compensated. 1. Léauté-Labrèze C, Prey S, Ezzedine K. Infantile haemangioma, part I: pathophysiology, epidemiology, clinical features, life cycle and associated structural abnormalities. J Eur Acad Dermatol Venereol. 2011;25(11):1245-1253. 2. Drolet BA, Frommelt PC, Chamlin SL, et al. Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Pediatrics. 2013;131 (1):128-140. 3. Hermans DJJ, Bauland CG, Zweegers J, van Beynum IM, van der Vleuten CJM. Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions. Br J Dermatol. 2013;168 (4):837-843. 4. Agence nationale de sécurité du médicament et des produits de santé. Autorisations temporaires d’utilisation. http://ansm.sante.fr/Activites /Autorisations-temporaires-d-utilisation-ATU/Qu-est-ce-qu-une-autorisation -temporaire-d-utilisation/%28offset%29/0. Accessed June 25, 2013. 5. Bégaud B, Evreux JC, Jouglard J, Lagier G. Imputation of the unexpected or toxic effects of drugs: actualization of the method used in France [in French]. Therapie. 1985;40(2):111-118. 6. Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med. 2015; 372(8):735-746.

COMMENT & RESPONSE

Physical Activity vs Health Education for Cognition in Sedentary Older Adults To the Editor Dr Sink and colleagues1 reported that a 24-month moderate-intensity physical activity program did not improve global or domain-specific cognitive function compared with a health education program in sedentary adults. We have concerns about their working definition of moderateintensity physical activity, the implementation and monitoring of the intervention, and the intensity of the physical activity intervention. The latest guidelines for older adults from the American College of Sports Medicine2 define moderate-intensity aerobic exercise training as 60% or greater maximal oxygen up˙ O2max or exercise intensity was not ˙ O2max). Because V take (V measured in this study, it is unknown whether the intervention met these latest guidelines. Cardiorespiratory stress testing would have allowed ˙ O2max and therefore to set approthe authors to determine V priate aerobic exercise training intensity. Stress testing provides important baseline information and is the criterion standard for assessing changes in cardiorespiratory fitness. Studies, such as the one by Tyndall et al,3 provide the necessary control measurements to determine whether improvements in cardiorespiratory fitness confer benefits on cognitive performance in older, healthy, sedentary jama.com

adults. Such testing is normally conducted in exercise studies in which cognition is a main outcome and is essential to provide new insights on dose intensity and exercise duration for brain health.4 In the study by Sink and colleagues,1 exercise sessions were unsupervised and adherence to the exercise program was measured by self-report along with 1 week of accelerometry data every 6 months. The authors claimed that the physical activity levels were maintained or increased during the 24-month period, but only difference scores were presented, making it unclear if the weekly dose of exercise recorded by the physical activity group actually met the study’s goal of 150 minutes/week. The dose intensity was low and training sessions (30 minutes) were short. The fact that those older than 80 years and those with the lowest physical activity levels benefited suggests that exercise dose was important. Physiological studies suggest that dose intensity much higher than that achieved is required to produce benefit.3,5 Exercise studies should address dose intensity. Marc J. Poulin, PhD, DPhil Gail A. Eskes, PhD Michael D. Hill, MD Author Affiliations: Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada (Poulin); Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada (Eskes); Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada (Hill). Corresponding Author: Marc J. Poulin, PhD, DPhil, Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, HMRB-210, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hill reported receiving grants from the Canadian Institutes of Health Research, HoffmannLaRoche Canada, and Covidien; being a board member for the Heart and Stroke Foundation of Alberta, Institute for Circulatory and Respiratory Health of the Canadian Institutes of Health Research, and Canadian Federation of Neurological Sciences; being a consultant to Merck; receiving payment for lectures from Hoffmann-LaRoche Canada, Servier Canada, and BMS Canada; owning stock in Calgary Scientific; and receiving salary awards from the Heart and Stroke Foundation of Alberta and Alberta Innovates Health Solutions. No other disclosures were reported. 1. Sink KM, Espeland MA, Castro CM, et al; LIFE Study Investigators. Effect of a 24-month physical activity intervention vs health education on cognitive outcomes in sedentary older adults: the LIFE randomized trial. JAMA. 2015;314 (8):781-790. 2. Chodzko-Zajko WJ, Proctor DN, Fiatarone Singh MA, et al; American College of Sports Medicine. American College of Sports Medicine position stand: exercise and physical activity for older adults. Med Sci Sports Exerc. 2009;41(7): 1510-1530. 3. Tyndall AV, Davenport MH, Wilson BJ, et al. The brain-in-motion study: effect of a 6-month aerobic exercise intervention on cerebrovascular regulation and cognitive function in older adults. BMC Geriatr. 2013;13:21. 4. Prakash RS, Voss MW, Erickson KI, Kramer AF. Physical activity and cognitive vitality. Annu Rev Psychol. 2015;66:769-797. 5. Vidoni ED, Johnson DK, Morris JK, et al. Dose-response of aerobic exercise on cognition: a community-based, pilot randomized controlled trial. PLoS One. 2015;10(7):e0131647.

In Reply The purpose of the Lifestyle Interventions and Independence for Elders (LIFE) study was to test whether a (Reprinted) JAMA January 26, 2016 Volume 315, Number 4

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of Tennessee - Knoxville User on 01/27/2016

415

Safety of Propranolol Therapy for Severe Infantile Hemangioma.

Safety of Propranolol Therapy for Severe Infantile Hemangioma. - PDF Download Free
86KB Sizes 2 Downloads 14 Views