Malaria Chemoprevention in the Postdischarge Management of Severe Anemia

Abstract

Background: Children who have been hospitalized with severe anemia in areas of Africa in which malaria is endemic have a high risk of readmission and death within 6 months after discharge. No prevention strategy specifically addresses this period.

Methods: We conducted a multicenter, two-group, randomized, placebo-controlled trial in nine hospitals in Kenya and Uganda to determine whether 3 months of malaria chemoprevention could reduce morbidity and mortality after hospital discharge in children younger than 5 years of age who had been admitted with severe anemia. All children received standard in-hospital care for severe anemia and a 3-day course of artemether-lumefantrine at discharge. Two weeks after discharge, children were randomly assigned to receive dihydroartemisinin-piperaquine (chemoprevention group) or placebo, administered as 3-day courses at 2, 6, and 10 weeks after discharge. Children were followed for 26 weeks after discharge. The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. Conditional risk-set modeling for recurrent events was used to calculate hazard ratios with the use of the Prentice-Williams-Peterson total-time approach.

Results: From May 2016 through May 2018, a total of 1049 children underwent randomization; 524 were assigned to the chemoprevention group and 525 to the placebo group. From week 3 through week 26, a total of 184 events of readmission or death occurred in the chemoprevention group and 316 occurred in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.54 to 0.78; P<0.001). The lower incidence of readmission or death in the chemoprevention group than in the placebo group was restricted to the intervention period (week 3 through week 14) (hazard ratio, 0.30; 95% CI, 0.22 to 0.42) and was not sustained after that time (week 15 through week 26) (hazard ratio, 1.13; 95% CI, 0.87 to 1.47). No serious adverse events were attributed to dihydroartemisinin-piperaquine.

Conclusions: In areas with intense malaria transmission, 3 months of postdischarge malaria chemoprevention with monthly dihydroartemisinin-piperaquine in children who had recently received treatment for severe anemia prevented more deaths or readmissions for any reason after discharge than placebo. (Funded by the Research Council of Norway and the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT02671175.).

Figure 1.. Screening, Randomization, and Follow-up.

All 1049 children who underwent randomization were included in the intention-to-treat analysis. Among the children who had screening failure, 2 children were older than 59.5 months at the time of screening (i.e., about 2 weeks before randomization), 1 had a history of hypersensitivity to a trial drug, 6 had sickle cell disease, 14 were receiving a prohibited medication or were enrolled in another study that used a prohibited medication, 79 were unable to adhere to the follow-up schedule, 2 had a history of cardiac disorders, and blood transfusion had not yet been completed in 38.

Figure 2 (facing page).. Primary Outcome and Other Efficacy Outcomes.

The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. The adjusted hazard ratios were adjusted for site, body weight, number of previous hospital admissions, syndrome at the time of admission (severe malarial anemia or severe nonmalarial anemia), age, hemoglobin level at randomization, distance to the hospital, and socioeconomic status. The widths of the confidence intervals have not been adjusted for multiplicity, so the intervals should not be used to infer definitive treatment effects. The bars and the point estimates for the confidence intervals correspond to the crude hazard ratios. Severe anemia was defined as a hemoglobin level of less than 5 g per deciliter, a hematocrit of less than 15%, or a clinical indication for blood transfusion. Severe malarial anemia was defined as severe anemia in the presence of any evidence of malaria infection detected by means of rapid diagnostic tests or microscopic examination. Severe malaria-specific anemia was defined as severe anemia in the presence of malaria infection detected by means of microscopic examination, with more than 5000 parasites per microliter. A secondary analysis of the primary outcome that excluded death or readmission due to trauma or cancer showed similar results because only one event in the chemoprevention group and no event in the placebo group was due to trauma or cancer.

Figure 3.. Primary Outcome According to Subgroup.

The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. The widths of the confidence intervals have not been adjusted for multiplicity, so the intervals should not be used to infer definitive treatment effects. Severe malarial anemia was defined as severe anemia in the presence of any evidence of malaria infection detected by means of rapid diagnostic tests or microscopic examination or, if no diagnostic test result was available, any treatment with parenteral antimalarial drugs in the hospital.