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Guideline Summary
Guideline Title
Best evidence statement (BESt). Growth hormone therapy in Duchenne muscular dystrophy.
Bibliographic Source(s)
Cincinnati Children's Hospital Medical Center. Best evidence statement (BESt). Growth hormone therapy in Duchenne muscular dystrophy. Cincinnati (OH): Cincinnati Children's Hospital Medical Center; 2009 Jul 20. 10 p. [52 references]
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Duchenne muscular dystrophy (DMD)

Guideline Category
Assessment of Therapeutic Effectiveness
Treatment
Clinical Specialty
Endocrinology
Family Practice
Medical Genetics
Neurology
Pediatrics
Intended Users
Advanced Practice Nurses
Physician Assistants
Physicians
Guideline Objective(s)

To provide recommendations for use of growth hormone in children with Duchenne muscular dystrophy

Target Population

Children with Duchenne muscular dystrophy (DMD)

Interventions and Practices Considered
  1. Growth hormone for the primary purpose of improving muscle function and strength was considered but not recommended
  2. Growth hormone for the primary purpose of short stature
Major Outcomes Considered
  • Lean body mass
  • Muscle function and strength
  • Growth velocity
  • Adverse effects of growth hormone therapy

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Search Strategy

  1. Original Search
    • OVID DATABASES
      MEDLINE, CINAHL, Cochrane Database for Systematic Reviews (CDSR)
    • OVID FILTERS
      Publication Date: 1996 to present
      Limits: English language and (humans or animals)
    • SEARCH TERMS & MeSH TERMS (MEDLINE & CINAHL)
      Patients/Population: exp Muscular Dystrophy, Duchenne/exp terms/
      limit to ("all child (0 to 18 years)" or all child <0 to 18 years>)(pediatr$ or child$).mp.
      Intervention/Exposure: exp Growth Hormone/ or exp Injections, Subcutaneous/ exp terms/
      Outcomes: exp Muscle Contraction/ or exp Muscle, Skeletal/ or muscle.mp. exp terms/
  1. Additional Searches
    • For protective effect of GH on bone density
      • OVID – All EBM Reviews - Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR, HTA, and NHSEED
        Search terms: growth hormone, in title AND bone density, keyword
        Limits: humans, English, no age limits
    • For effect of GH on growth in patients on glucocorticoids
      • OVID – MEDLINE
        Search terms: growth hormone, focus of study AND (juvenile idiopathic arthritis OR juvenile rheumatoid arthritis), focus of study
        Limits: humans, English, 0 to 18 yrs
    • For cost and cost-effectiveness of GH therapy
      • OVID – MEDLINE
        Search terms: (Cost-Benefit Analysis/ OR Health Care Costs/ or Drug Therapy/) AND growth hormone
        Limits: humans, English, 0 to 18 yrs
  1. Additional Articles – identified from reference lists and clinicians
Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Table of Evidence Levels

Quality Level Definition
1a† or 1b† Systematic review, meta-analysis, or meta-synthesis of multiple studies
2a or 2b Best study design for domain
3a or 3b Fair study design for domain
4a or 4b Weak study design for domain
5 Other: General review, expert opinion, case report, consensus report, or guideline

†a = good quality study; b = lesser quality study

Note: Full tables of evidence grades and strength of recommendations are available in separate documents (see the "Availability of Companion Documents" field).

Methods Used to Analyze the Evidence
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Not stated

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Not stated

Rating Scheme for the Strength of the Recommendations

Table of Recommendation Strength

Strength Definition
"Strongly recommended" There is consensus that benefits clearly outweigh risks and burdens (or vice-versa for negative recommendations).
"Recommended" There is consensus that benefits are closely balanced with risks and burdens.
No recommendation made There is a lack of consensus to direct development of a recommendation.
Dimensions: In determining the strength of a recommendation, the development group makes a considered judgment in a consensus process that incorporates critically appraised evidence, clinical experience, and other dimensions as listed below.
  1. Grade of the Body of Evidence
  2. Safety/Harm
  3. Health benefit to the patients (direct benefit)
  4. Burden to patient of adherence to recommendation (cost, hassle, discomfort, pain, motivation, ability to adhere, time)
  5. Cost-effectiveness to healthcare system (balance of cost/savings of resources, staff time, and supplies based on published studies or onsite analysis)
  6. Directness (the extent to which the body of evidence directly answers the clinical question [population/problem, intervention, comparison, outcome])
  7. Impact on morbidity/mortality or quality of life

Note: Full tables of evidence grades and strength of recommendations are available in separate documents (see the "Availability of Companion Documents" field).

Cost Analysis

Published cost analyses were reviewed.

Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation

Reviewed by the Division of Health Policy & Clinical Effectiveness

Recommendations

Major Recommendations

The quality of the evidence (1a to 5) and strength of the recommendation (strongly recommended, recommended, or no recommendation) are defined at the end of the "Major Recommendations" field.

  1. It is recommended, because of insufficient evidence on the benefits and risks of growth hormone (GH) therapy in children with Duchenne muscular dystrophy (DMD), that GH not be prescribed for the primary purpose of improving muscle function and strength (Myers et al., 2007 [2b]; Hansen et al., 2005 [2b]; Cittadini et al., 2003 [2b]; Liu et al., 2003 [2b]; Schibler et al., 2003 [2b]; Carrel et al., 2002 [2b]; Vahl et al., 2000 [2b]; Carrel et al., 1999 [2b]; Myers et al., 1999 [2b]; Osterziel et al., 1998 [2b]; Cuneo et al., 1991 [2b]; Schweizer et al., 2007 [3a]; Carroll et al., 2004 [3b]; Merlini et al., 1988 [5]; Local Consensus [5]). See Appendix in the original guideline document.

    Note: Several small randomized controlled trials of GH therapy have been conducted in diverse study populations to evaluate lean body mass and muscle strength and function. Administration of GH for as long as four years appears to result in increased lean body mass, but associated improvements in muscle strength or function are not consistently observed. These study populations have included children with DMD, adults with Becker muscular dystrophy, children and adults with GH deficiency (GHD), pre-pubertal children born small for gestational age, children with Prader-Willi syndrome, children with cystic fibrosis, healthy young males and adults with cardiomyopathy (Liu et al., 2008 [1a]; de Lind van Wijngaarden et al., 2009 [2b]; Myers et al., 2007 [2b]; Chihara et al., 2006 [2b]; Hansen et al., 2005 [2b]; Cittadini et al., 2003 [2b]; Liu et al., 2003 [2b]; Schibler et al., 2003 [2b]; Carrel et al., 2002 [2b]; Vahl et al., 2000 [2b]; Carrel et al., 1999 [2b]; Myers et al., 1999 [2b]; Osterziel et al., 1998 [2b]; Cuneo et al., 1991 [2b]; Eiholzer et al., 2009 [4b]). See Appendix in the original guideline document.

  2. It is recommended, for children with DMD who exhibit severe short stature and/or severe slowing of growth rate1 (such as those receiving long-term glucocorticoid treatment), that GH for treatment of short stature be discussed with the patient and family as a treatment option, and include in this discussion the potential for a positive impact on lean muscle mass (Bryant et al., 2002 [1a]; Rider & Leschek, 2008 [2b]; Simon et al., 2007 [2b]; Rutter et al., 2008 [4b]; Allen et al., 1998 [4b]; Local Consensus [5]).

    Note 1: Use of GH is Food and Drug Administration (FDA)-approved for children who exhibit growth failure or short stature due to growth hormone deficiency or idiopathic short stature. The evidence for these indications has been summarized elsewhere (Bryant et al., 2002 [1a]).

    Note 2: Use of GH therapy has shown beneficial effects for growth in patients receiving long-term glucocorticoid treatment for juvenile idiopathic arthritis (JIA) with adverse effects limited to glucose intolerance not requiring insulin therapy in some patients (Bechtold et al., 2007 [2b]; Simon et al., 2007 [2b]; Saha et al., 2004 [3b]; Allen et al., 1998 [4b]).

    Note 3: A cohort at Cincinnati Children's Hospital of eight boys with DMD and severe steroid-induced growth failure were treated with GH and showed an improvement in growth velocity within the first year from 0.5 cm/year (range 0 to 1.8 cm/year) to 5.4 cm/year (range 3.2 to 8.4 cm/year). There was improvement in neuromuscular and lung function among some younger boys (ages 9 to 13), and lack of deterioration in these functions in some older boys (ages 14 to 17). Improvements in neuromuscular and pulmonary function are in contrast to the natural history of children with DMD above nine years of age who show progressive decline in motor and pulmonary function. Mild progression of scoliosis was observed in two patients (Rutter et al., 2008 [4b]).

    Note 4: A key consideration in the shared decision-making process is the cost of GH therapy which is in the range of $20,000 to $30,000 per year, or about $42 per mg (Bryant et al., 2002 [1a]; Cuttler et al., 2005 [4a]).

    Note 5: Lack of sufficient studies of the safety of GH therapy in DMD warrants close monitoring for changes of neuromuscular function, development or progression of scoliosis, abnormalities in glucose metabolism, benign intracranial hypertension, and abnormalities in cardiopulmonary function (Myers et al., 2007 [2b]; Simon et al., 2007 [2b]; Osterziel et al., 1998 [2b]; Fideleff et al., 2008 [3b]; Rutter et al., 2008 [4b]; Allen et al., 1998 [4b]).

    Note 6: GH improves bone mineral density in adults with GHD (Bex et al., 2002 [2a]; Baum et al., 1996 [2b]; O'Halloran et al., 1993 [2b]). Studies in children evaluating the protective effects of GH on bone mineral density (BMD), as well as on bone mineral content (BMC), strength-strain index (SSI), markers of bone formation and bone resorption, and bone cross-sectional area demonstrate inconsistent results (Grote et al., 2006 [2b]; Schweizer et al., 2007 [3a]; Fideleff et al., 2008 [3b]; Saha et al., 2004 [3b]; Simon et al., 2003 [3b]; Rooney et al., 2000 [3b]; Touati et al., 2000 [3b]; Bechtold et al., 2005 [4b]).

1Severe short stature is defined as height < 3 standard deviations below the norm. Severe growth deceleration is defined as height velocity < 2 standard deviations below the norm over 12 months (Rosenfeld & Cohen, 2008 [5]).

Definitions:

Table of Evidence Levels

Quality Level Definition
1a† or 1b† Systematic review, meta-analysis, or meta-synthesis of multiple studies
2a or 2b Best study design for domain
3a or 3b Fair study design for domain
4a or 4b Weak study design for domain
5 Other: General review, expert opinion, case report, consensus report, or guideline

†a = good quality study; b = lesser quality study

Table of Recommendation Strength

Strength Definition
"Strongly recommended" There is consensus that benefits clearly outweigh risks and burdens (or vice-versa for negative recommendations).
"Recommended" There is consensus that benefits are closely balanced with risks and burdens.
No recommendation made There is a lack of consensus to direct development of a recommendation.
Dimensions: In determining the strength of a recommendation, the development group makes a considered judgment in a consensus process that incorporates critically appraised evidence, clinical experience, and other dimensions as listed below.
  1. Grade of the Body of Evidence
  2. Safety/Harm
  3. Health benefit to the patients (direct benefit)
  4. Burden to patient of adherence to recommendation (cost, hassle, discomfort, pain, motivation, ability to adhere, time)
  5. Cost-effectiveness to healthcare system (balance of cost/savings of resources, staff time, and supplies based on published studies or onsite analysis)
  6. Directness (the extent to which the body of evidence directly answers the clinical question [population/problem, intervention, comparison, outcome])
  7. Impact on morbidity/mortality or quality of life

Note: Full tables of evidence grades and strength of recommendations are available in separate documents (see the "Availability of Companion Documents" field).

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

References Supporting the Recommendations
Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for each recommendation (see the "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits
  • Improved stature and improvement in growth velocity in children with short stature or growth failure
  • Growth hormone may have a positive impact on lean muscle mass.
Potential Harms

Adverse effects of growth hormones as reported in the studies reviewed are discussed in the Appendix of the original guideline document.

Qualifying Statements

Qualifying Statements

This Best Evidence Statement addresses only key points of care for the target population; it is not intended to be a comprehensive practice guideline. These recommendations result from review of literature and practices current at the time of their formulation. This Best Evidence Statement does not preclude using care modalities proven efficacious in studies published subsequent to the current revision of this document. This document is not intended to impose standards of care preventing selective variances from the recommendations to meet the specific and unique requirements of individual patients. Adherence to this Statement is voluntary. The clinician in light of the individual circumstances presented by the patient must make the ultimate judgment regarding the priority of any specific procedure.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Living with Illness
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
Cincinnati Children's Hospital Medical Center. Best evidence statement (BESt). Growth hormone therapy in Duchenne muscular dystrophy. Cincinnati (OH): Cincinnati Children's Hospital Medical Center; 2009 Jul 20. 10 p. [52 references]
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2009 Jul 20
Guideline Developer(s)
Cincinnati Children's Hospital Medical Center - Hospital/Medical Center
Source(s) of Funding

Cincinnati Children's Hospital Medical Center

Guideline Committee

Not stated

Composition of Group That Authored the Guideline

Group/Team Members: Brenda Wong, MD, Neurology; Meilan Rutter, MD, Endocrinology; Susan Rose, MD, Endocrinology

Clinical Effectiveness Support: Eloise Clark, MPH, MBA, Evidence Facilitator; Barbarie Hill, MLS, Pratt Library; Danette Stanko-Lopp, MA, MPH, Epidemiologist; Karen Vonderhaar, MS, RN, Methodologist

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available from the Cincinnati Children's Hospital Medical Center External Web Site Policy.

Print copies: For information regarding the full-text guideline, print copies, or evidence-based practice support services contact the Cincinnati Children's Hospital Medical Center Health James M. Anderson Center for Health Systems Excellence at EBDMInfo@cchmc.org.

Availability of Companion Documents

The following are available:

  • Judging the strength of a recommendation. Cincinnati (OH): Cincinnati Children's Hospital Medical Center; 2008 Jan. 1 p.
  • Grading a body of evidence to answer a clinical question. Cincinnati (OH): Cincinnati Children's Hospital Medical Center; 1 p.
  • Table of evidence levels. Cincinnati (OH): Cincinnati Children's Hospital Medical Center; 2008 Feb 29. 1 p.

Print copies: For information regarding the full-text guideline, print copies, or evidence-based practice support services contact the Cincinnati Children's Hospital Medical Center Health James M. Anderson Center for Health Systems Excellence at EBDMInfo@cchmc.org.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on July 23, 2010.

Copyright Statement

This NGC summary is based on the original full-text guideline, which is subject to the following copyright restrictions:

Copies of this Cincinnati Children's Hospital Medical Center (CCHMC) External Web Site Policy Best Evidence Statement (BESt) are available online and may be distributed by any organization for the global purpose of improving child health outcomes. Examples of approved uses of the BESt include the following:

  • Copies may be provided to anyone involved in the organization's process for developing and implementing evidence based care.
  • Hyperlinks to the CCHMC website may be placed on the organization's website.
  • The BESt may be adopted or adapted for use within the organization, provided that CCHMC receives appropriate attribution on all written or electronic documents.
  • Copies may be provided to patients and the clinicians who manage their care.

Notification of CCHMC at EBDMInfo@cchmc.org for any BESt adopted, adapted, implemented or hyperlinked by the organization is appreciated.

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