Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study

Abstract

Background: DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) was a Phase 3, randomized, double-blind, placebo-controlled study conducted in children with sickle cell anemia at 51 sites in 13 countries across four continents. Procedure: Data from DOVE were assessed for regional differences in subject phenotype and treatment. Demographics, baseline clinical and laboratory data, hydroxyurea (HU) use, vaso-occlusive crisis (VOCs; composite endpoint of painful crisis or acute chest syndrome (ACS)), serious adverse events (SAEs), hospitalization, and treatments were compared across the Americas, Europe, North Africa/Middle East, and Sub-Saharan Africa (SSA). Results: Race, body mass index, and blood pressures differed by region. Pre-enrollment VOCs were highest in the Americas. For subjects not on HU, baseline hemoglobin was lowest in SSA; reticulocyte count was lowest in the Americas. Within SSA, Kenya subjects presented higher baseline hemolysis. Painful crisis was the most common SAE, followed by ACS in the Americas and infections in other regions. VOC rate and percentage of VOC hospitalizations were highest in Europe. Regardless of region, most VOCs were treated with analgesics; approximately half were treated with intravenous fluids. The proportion of VOC-related transfusions was greatest in Europe. Lengths of hospital stay were similar across regions. Conclusions: Overall differences in SAEs and hospitalization for VOCs may be due to cultural diversities, resource utilization, disease severity, or a combination of factors. These data are of importance for the planning of future trials in SCA in a multinational setting.

Evidence-based interventions implemented in low-and middle-income countries for sickle cell disease management: A systematic review of randomized controlled trials

“…The review included 30 papers that reported on 29 RCTs conducted in 14 LMICs. Heeney et al [ 31 ] and Inusa et al [ 17 ] were two papers reporting on the same study. Seven studies were conducted each in Nigeria and Brazil, 5 studies each in Jamaica and Uganda, 2 studies each in Ghana, Egypt and Lebanon, and 1 study each in Iran, Kenya, Sudan, Senegal, Turkey, Colombia, Tanzania and India.…”

“…Seven studies were conducted each in Nigeria and Brazil, 5 studies each in Jamaica and Uganda, 2 studies each in Ghana, Egypt and Lebanon, and 1 study each in Iran, Kenya, Sudan, Senegal, Turkey, Colombia, Tanzania and India. Five studies were conducted at multiple sites; Hankins et al [ 32 ] and Kutlar et al [ 47 ] conducted studies in Jamaica, US, and Brazil; Inusa et al [ 17 ] and Heeney et al [ 31 ] conducted studies in Ghana, Kenya, Belgium, UK, Italy, Canada, US, Brazil, Saudi Arabia, Egypt, Oman, Lebanon, Turkey; Kutlar et al [ 46 ] conducted studies in Lebanon, Egypt, Jamaica; Misra et al [ 16 ] conducted studies in Panama and Colombia. Of these LMICs, 18 studies were conducted in Africa—Nigeria (n = 7), Uganda (n = 5), Egypt (n = 1), Tanzania (n = 1), Ghana (n = 1), Sudan (n = 1), Senegal (n = 1), Kenya (n = 1); 8 studies were conducted in Latin America—Brazil (n = 7) and Colombia (n = 1); 5 were conducted in the Caribbean–Jamaica (n = 5); 2 were conducted in the Middle East—Iran (n = 1) and Lebanon (n = 1) and 2 studies were conducted in Europe and Asia—India (n = 1) and Turkey (n = 1).…”

“…Random sequence generation and allocation concealment together represent selection bias. More than 75% of the studies had a low risk of selection bias due to random sequence generation [ 15 – 17 , 31 – 44 , 46 – 48 , 51 – 56 , 58 ]; about 62.5% of the studies also had a low risk of selection bias due to allocation concealment [ 15 , 17 , 33 , 35 – 42 , 47 , 51 – 54 , 56 , 61 ]. Less than 50% of studies had a low risk of performance bias due to blinding of participants and personnel [ 15 , 32 , 35 – 39 , 42 , 43 , 47 , 51 – 54 , 56 ]; about 40% of studies had a low risk of detection bias due to blinding of outcome assessment [ 32 , 33 , 36 , 39 , 40 , 47 , 51 – 53 , 56 , 61 , 62 ]; more than 75% of the studies had a low risk of attrition bias due to incomplete outcome data [ 16 , 32 – 42 , 44 – 47 , 49 , 51 – 56 , ...…”

Novel findings from the multinational DOVE study on geographic and age‐related differences in pain perception and analgesic usage in children with sickle cell anaemia

“…Although patient‐reported pain rates were similar in all regions, participants from regions of the Americas and Europe reported significantly higher pain intensity than participants from Africa and the Middle East (Table ). Values for baseline haematological laboratory markers (Inusa et al , ) showed no statistically significant relationship with reported pain rate or pain intensity in any age group (data not shown).…”

“…Due to concerns with usability of the ePRO, diary‐reported pain rate and intensity were only evaluated in participants aged ≥7 years. Rate of ePRO‐reported opioid (Inusa et al , )analgesic use was similarly analysed in participants aged ≥7 years. To accurately capture pain intensity, only the days on which pain was reported were included in this analysis.…”