NT-pro brain natriuretic peptide levels and the risk of death in the cooperative study of sickle cell disease

Abstract

Epidemiological studies support a hypothesis that pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) that is associated with a high risk of death and evolves as a complication of haemolytic anaemia. This fundamental hypothesis has been recently challenged and remains controversial. In order to further test this hypothesis in a large and independent cohort of SCD patients we obtained plasma samples from the Cooperative Study of Sickle Cell Disease (CSSCD) for analysis of a biomarker, N-terminal-pro brain natriuretic peptide (NT-proBNP), which is elevated in the setting of pulmonary arterial and venous hypertension. A NT-pro-BNP value previously identified to predict PH in adults with SCD was used to determine the association between the risk of mortality in 758 CSSCD participants (428 children and 330 adults). An abnormally high NT-proBNP level ≥160ng/l was present in 27·6% of adult SCD patients. High levels were associated with markers of haemolytic anaemia, such as low haemoglobin level (P<0·001), high lactate dehydrogenase (P<0·001), and high total bilirubin levels (P<0·007). A NT-proBNP level ≥160ng/l was an independent predictor of mortality (RR 6·24, 95% CI 2·9-13·3, P<0·0001). These findings provide further support for an association between haemolytic anaemia and cardiovascular complications in this patient population.

Figure 1. Plasma NT-proBNP Assessment in the Cooperative Study of Sickle Cell Disease

The patient population was selected from CSSCD study subjects enrolled between September 1978 and 1988 who participated in Phase 2 (paediatric cohort, n=467) or Phase 2a (adult cohort, n=395), and was based on the availability of one or more serum samples stored at the study repository. A total of 758 patients with sickle cell disease (428 or 91.6% of patients in the paediatric cohort and 330 or 83.5% of patients in the adult cohort) who had at least one NT-proBNP level measured between 1989 and 1998 were selected for our analysis (w/ BNP). A total of 1,269 samples were available for the analysis. ¹Age at entry: < 6 months (infants), 6 months-9 years (children), 10–19 (adolescents), = 20 years (adults) ²Includes samples with unknown sampling dates: n=114 (15%) for infant cohort, n=73 (14%) for adult cohort

Figure 2. Distribution of Patients with a High NT-proBNP Level ≥ 160 ng/l According to Age

The prevalence of a high NT-proBNP level increases with age in adults. In the paediatric cohort this trend does not occur given the physiologically higher normal NT-proBNP levels in children, especially during the first year of life.

Figure 3. Kaplan–Meier Survival Curves According to NT-proBNP Level

The survival rate (A) and age of death (B) were significantly higher among patients with a low plasma NT-proBNP level than among those with a high plasma NT-proBNP level (P< 0.001).