Hydroxyurea For the Management of Childhood SCD in Kenyan County Hospitals Hydroxyurea for SCD Panel.

Hydroxyurea For the Management of Childhood SCD in Kenyan County

Hospitals

Hydroxyurea for SCD Panel

Objectives• To understand the background to the emergence of

hydroxyurea as a therapy for SCD and review the evidence available to inform decision making

– Should Hydroxyurea be promoted for prophylactic treatment of SCD in children aged <5 years being managed in County hospitals• At what stage of disease might introduction be

considered• Are there any specific conditions for using the drug

• To provide preliminary recommendations to MoH on use of HU

Outline• Background

• Evidence

• Summary on quality of evidence (as per panel discussions)

• Panel deliberations

Burden of SCD• It is estimated 312 000 neonates globally are born

yearly with SCD (HbS) homozygous type (Piel FB 2013).

• 75% of the burden is in sub-Saharan Africa (WHO 2006)

• Mortality is high in children aged between 6 months and 3 years (Leikin SL 1998,Rogers DW 1978)

• High mortality rate of 7.3 (4.8-11.0)per 100 Patient years Of Observation in <5 years in Tanzania (Makani J 2011)

Existing guidelines

GOK Clinical Guidelines 2009 (expert meeting):

– Hydroxyurea only for (adult) patients with more than 3 painful crises in a year

– Supportive care (analgesics, supplementary folic , malaria prophylaxis when travelling to malaria endemic zone, penicillin prophylaxis)

Guideline relevant question

population Intervention Control Outcomes

Children( <5 years) with Severe SCD OR

Children (<5 years) with SCD at first presentation in the clinics

Hydroxyurea Conventional care

Critical; Mortality,Hospitalizations

Placebo Important; Pain episodes, Toxicity

Study selection

IDENTIFICATION(Pubmed,clinical trials web,

Cochrane Lib.)

SCREENING(Titles and abstracts)

ELIGIBILITY(full articles assessment)

INCLUDED(Studies included for analysis)

N=98

N=44

N=19

N=191 Syst. review

2 RCT14 observational

studies2 NIH reports

BABY-HUG TRIAL 2011Population Intervention

(n=96)Comparator(n=97)

Outcomes

Children aged 9-18months irrespective of clinical severity

Hydroxyurea(Fixed dose of

20mg/kg)

Placebo Primary Outcomes• Splenic function• Renal function

Secondary Outcomes• Adverse clinical

events• Hematological • Toxic effects

Results (secondary outcomes) Outcome (total events)

HU Group (n=96) Placebo Group (n=97)

Hazard Ratio(95% CI)

Pain 177 375 0.59(0.42-0.83)

Dactylitis 24 123 0.27(0.15-0.50)

Acute Chest Syndrome

8 27 0.36(0.15-0.87)

Hospitalizations 232 324 0.73(0.53-1.00)

Transfusion 35 63 0.55(0.32-0.96)

Mild-ModerateNeutropenia

107 times in 45 children

34 times in 18 children

3.0(1.7-5.1)

SummaryOutcome Hazard ratio(95% CI) Quality Of Evidence

Mortality Limited evidence -

Hospitalizations 0.73(0.53-1.00)Low

Toxicity(Mild-Moderate Neutropenia )

3.0(1.7-5.1) Low

Pain Episodes 0.59(0.42-0.83) Moderate

Consensus on balance of benefits versus harms: Hydroxyurea vs no HU

Mild form of disease Severe form of disease

Monitoring available Harms outweigh benefits (Majority)

Benefits outweigh harms (Unanimous)

Monitoring not available Harms outweigh benefits (Unanimous)

•Benefits outweigh harms (Considerable number)

•Benefits balances harms (Half of the Panel)

Panel proposed definition of severe disease as possible indication for initiating HU

• Pain crises ( >3 /year)• Primary stroke• Transfusions( ≥2/year)• Acute chest syndrome• Hospitalizations which are Sickle cell Disease

related(to be specified further)• Splenic sequestration

Panel proposed Monitoring Requirement

Where monitoring comprises:• Monthly monitoring at the minimum Monitoring includes:• Complete blood count• Hemoglobin• White blood cell count especially the neutrophils• Platelet counts

Panel view on formulations of HU

• Currently 500mg available• Recommendation: Appropriate capsules

should be procured of different strengths (200mg, 300mg, 400mg) prior to widespread implementation of HU in GoK hospitals able to provide minimum monitoring.

Areas for research

• Need to get better data on the burden of SCD in the country

• Studies on effect of Hydroxyurea on morbidity and mortality (including harms) are required

• Data on long term effects of HU are required

Draft Recommendation

‘Hydroxyurea at a standard dose of 20mg/kg/day should be considered for use in children below 5 years for management of severe form of sickle cell disease where minimum monitoring conditions and appropriate formulation are available’