<scp>N</scp>‐terminal pro‐<scp>B</scp>‐type natriuretic peptide, tricuspid jet flow velocity, and death in adults with sickle cell disease
Authors: Marein Schimmel, Eduard J. van Beers, Charlotte F.J. van Tuijn, Erfan Nur, Anita W. Rijneveld, Melvin R. Mac Gillavry, Dees P.B. Brandjes, John‐John B. Schnog, Bart J. Biemond
Journal: American Journal of Hematology (2015)

Both elevated N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels (>160 pg/mL) and elevated tricuspid regurgitant jet flow velocity (TRV ≥2.5 m/sec) have been related to the presence of (echocardiography defined) pulmonary hypertension and the risk of early death in patients with sickle cell disease (SCD) [1–3]. Recent guidelines advise to use NT-proBNP levels to identify patients at risk for mortality when trans-thoracic Doppler to measure TRV is not available 4. We studied the relation between elevated NT-proBNP levels (>160 pg/mL), elevated TRV (≥2.5 m/sec), and the risk of mortality in a cohort of 85 adult outpatients with sickle cell anemia (HbSS) or compound heterozygous states such as HbSβ0-thalassemia (HbSβ0-thal), HbSβ+-thalassemia (HbSβ+-thal), and sickle-hemoglobin C (HbSC) 5. Patients were excluded if they had a history of chronic obstructive pulmonary disease or poorly controlled asthma, congestive heart failure, painful crisis, or acute chest syndrome in the preceding 4 weeks and/or blood transfusion within 3 months prior to performing study related tests. The mean age at baseline analysis was 34 years (median 30; interquartile range (IQR): 23–47). We followed patients for a median of 82 months (IQR 75–85) during which three patients were lost to follow-up and 12 patients (11 HbSS and 1 HbSβ0-thal) died. Median age at death was 53 years (IQR 37–60). Baseline trans-thoracic echocardiographic results were available from 81 patients and echocardiography was repeated every 2 years in steady-state conditions. TRV ≥2.5–2.9 m/sec was considered elevated, a TRV>2.9 m/sec severely elevated, and TRV was considered normal in patients with trace or no tricuspid regurgitation (undetectable values were assigned a value of 1.3 m/sec) 1. In 25 patients (31%) a TRV ≥2.5–2.9 m/sec was measured at baseline (22 (39%) HbSS/HbSβ0-thal and 3 (12%) HbSC/HbSβ+-thal patients) and a TRV >2.9 m/sec in two HbSS patients. Twenty of 56 patients with a TRV <2.5 m/sec at baseline developed an increased TRV (≥ 2.5 m/sec) during follow-up (5.3% per year). Having a TRV ≥ 2.5 m/sec measured at baseline did not result in a significant increased hazard rate (HR) for mortality for these patients as calculated by Cox regression analysis (HR 1.6 [confidence interval (CI) 0.5–5.2], P = 0.4). Figure 1A. Introducing age in a multi-variate Cox-regression analysis did not change the HR for mortality in patients with TRV ≥2.5 m/sec (HR 1.1 [CI 0.3–3.7], P = 0.9). The HR for mortality in a subgroup of HbSS/HbSβ0-thal patients with a TRV ≥ 2.5 m/sec was 1.1 [CI 0.4–3.4], P = 0.9. Plasma NT-proBNP levels were available from 77 patients at baseline after quantitation in EDTA anticoagulated plasma employing an ELISA (Roche). In 14 patients a NT-proBNP value ≥160 pg/mL was measured (all HbSS/HbSβ0-thal patients), of whom 50% also had a TRV level of ≥2.5 m/sec at baseline. Figure 1C. Using the previously defined cut-off value for NT-proBNP of 160 pg/mL as a risk factor for early death 6, patients with elevated NT-proBNP levels had a HR of death of 10.0 [CI 2.9–34.4], P < 0.001, compared to patients with normal NT-proBNP levels (<160 pg/mL). Figure 1B. In the HbSS/HbSβ0-thal group alone this HR was 6.3 [CI 1.8–21.6], P = 0.003. Given the low number of deaths during follow-up, a multivariate Cox-regression survival analysis was performed for only two variables at the time, always including NT-proBNP levels. None of analyzed variables that may affect NT-proBNP plasma levels (such as age, renal function, TRV, ferritin, or hemoglobin levels) could solely explain the increased HR for death for patients with NT-proBNP plasma levels of ≥160 pg/mL. Therefore, an elevated NT-proBNP level identifies especially HbSS/HbSβ0-thal patients at high risk of death independent of an elevated TRV. We hypothesize that NT-proBNP levels are likely to be determined by several prognostic factors in SCD such as diastolic dysfunction, hypoxia, age, rate of hemolysis, inflammation, renal function and iron overload. NT-proBNP might therefore be useful as a simple prognostic biomarker in the clinically asymptomatic state reflecting the severity of the generalized vasculopathy and organ dysfunction in SCD. Relation between mortality and tricuspid regurgitant jet flow velocity and levels of N-terminal pro-B type natriuretic peptide. A: Kaplan–Meier survival analysis of risk of mortality for sickle cell patients with TRV ≥ 2.5 m/sec versus patients with TRV < 2.5 m/sec. The death rate for patients with a TRV ≥ 2.5 m/sec was 20% versus 12.5% for patients with a TRV < 2.5 m/sec (Hazard ratio of 1.6 [CI 0.5–5.2], P = 0.4). B: Kaplan–Meier survival analysis of risk of mortality for sickle cell patients with NT-proBNP levels ≥ 160 pg/mL versus patients with NT-proBNP levels < 160 pg/mL. The hazard rate for death rate for patients with NT-proBNP levels ≥ 160 pg/mL was 10.0 [CI 2.9–34.4], P < 0.001), compared to patients with NT-proBNP levels < 160 pg/mL. C: Distribution of levels of NT-proBNP in deceased patients and patients who survived according to baseline values of tricuspid regurgitant jet flow velocity. Levels between survivors were not significantly different (P = 0.394), as were levels between non-survivors (P = 0.109). Importantly, both the lack of an association of TRV to mortality and the relatively low mortality in our cohort, as well as in a recent European SCD cohort, are in contrast with earlier studies in the United States (US) 1-3. As TRV was significantly related to mortality in SCD in a study of comparable size 2, our relatively small sample size is not likely to be an explanation for this conflicting observation. Also the relative low number of patients with severely elevated TRV in our cohort is unlikely to explain these differences as mortality was also high in patients with TRV between 2.5 and 2.9 m/sec in the NIH PHT Screening Study. Although exclusion of patients on a chronic transfusion program as well as the relatively younger age of our cohort in comparison to the US cohorts may, at least in part, explain some of the discrepancies, both the prevalence of a TRV ≥2.5 m/sec as well as the incidence of TRV elevation during follow-up were comparable with these cohorts 2. It is therefore unclear at this time what causes the difference in mortality between our cohort and the US cohorts. Factors such as genetic differences, differences in study inclusion criteria, health care organization, and accessibility may all contribute. In the present study we demonstrate that elevated NT-proBNP levels were strongly associated with death in SCD, independent of an elevated TRV. Whether initiating treatment with hydroxycarbamide or other intensifying treatments of sickle cell patients with increased levels of NT-proBNP results in clinical benefit should be subject of prospective clinical trials. M. Schimmel and B.J. Biemond had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; Study concept and design: JS, DB, MMacG, and BB; acquisition of data: CvT, EvB, EN, AR, MMacG, and MS; (Statistical) analysis and interpretation of data: MS, EvB, and BB; Drafting of the manuscript: MS, EvB, JS, and BB; critical revision of the manuscript for important intellectual content: all named co-authors; study supervision: EvB, JS, BB, and DB. Marein Schimmel,1,2* Eduard J. van Beers,2 Charlotte F.J. van Tuijn,2 Erfan Nur,2Anita W. Rijneveld,3 Melvin R. Mac Gillavry,1 Dees P.M. Brandjes,1John-John B. Schnog,4,5 and Bart J. Biemond2;on behalf of the CURAMA study group 1Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands; 2Department of Clinical Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 3Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands; 4Department of Hematology/Oncology, Sint Elisabeth Hospital, Willemstad, Curacao; 5Department of Immunology, Red Cross Blood Bank Foundation, Willemstad, Curacao