OBJECTIVES : Sickle-cell disease (SCD) is one of the most prevalent inherited diseases. Previous research suggests a relationship between Vaso-Occlusive Crises (VOC), acute painful episodes, and death. However, the time-varying effect of VOC on these outcomes prevents the establishment of a causal relationship using classically adjusted models. This study assessed the effect of VOC in the previous year on occurrence of death and the frequently reported complications using an Inverse Probability Weighted Marginal Structural Model (IPW-MSM).

METHODS : Prevalent patients with SCD between 2008 and 2017, their vital status and complications were identified using ICD-10 diagnosis codes recorded in NHS England's Hospital Episode Statistics database linked to the Office for National Statistics Mortality Data. The causal effect of VOC categorized into 3 groups (0,1-2,3+) on each complication and death was estimated using IPW-MSM Cox models approximated by weighted pooled logistic regressions. The weights were estimated using the probability of being in each VOC category with a multinomial logistic model, and the probability of being censored with a logistic model. These models were adjusted for age, gender, ethnicity, complications and comorbidities.

RESULTS : A total of 15,076 SCD patients were included with the occurrence of 1,141(8%) deaths, 4,097(27%) Acute Chest Syndrome, 1,571(10%) gallstones, 1,295(9%) Avascular Necrosis, 1,098(7%) sepsis and 1,037(7%) cardiomegaly during the follow-up. The Hazard Ratios of 1-2 VOCs versus 0 VOC and 3+VOCs versus 0 VOC were estimated at 1.44(95% CI:1.15;1.81) and 4.50(2.91;6.97) for death, at 2.98(2.64;3.37) and 5.51(3.67;8.27) for ACS, at 2.60(1.78;3.81) and 2.20(1.43;3.41) for gallstones, at 1.86(1.33;2.58) and 2.07(1.05;4.09) for AVN, at 1.91(1.45;2.52) and 2.11(1.21;3.67) for sepsis and at 1.36(1.04;1.77) and 2.48(1.54;3.99) for cardiomegaly.

CONCLUSIONS : Experiencing 3+ VOCs per year are associated with a higher risk of death and complications. Reducing the number of VOCs experienced or preventing patients from reaching 3 VOCs may significantly reduce the occurrence of death and most complications.