Predictive Factors for Survival in Sickle Cell Disease: A Cohort Study Using Etendard Data
Authors: Savale Laurent , Loko Gylna , Lionnet François , Maitre Bernard , Habibi Anoosha , Inamo Jocelyn , Bachir Dora , Driss Françoise , Audard Vincent , Audureau Etienne , Humbert Marc , Simonneau Gerald , Galactéros Frédéric , Parent Florence , Bartolucci Pablo 
Published: October 2019

Abstract
Introduction
The prospective ETENDARD study (NCT00434902) evaluated 398 outpatients with sickle cell disease (SCD) enrolled between February 2007 and March 2009 at referral centers in France. All patients were homozygous for hemoglobin S or had Sβ0 thalassemia. This study estimated the prevalence of pulmonary hypertension (PH) related to SCD to be 6%, based on the presence of a tricuspid regurgitation velocity (TRV) ≥2.5 m/s and a mean pulmonary arterial pressure (mPAP) measured by right-sided heart catheterization (RHC) ≥25 mmHg (Parent et al, New Engl J Med 2011). The long-term prognostic value of TRV≥2.5 m/s according to the level of mPAP measured by RHC has not been clearly established.
Methods
Using updated 10-year follow up data from the ETENDARD cohort study, we analyzed the overall survival of patients according to their TRV/mPAP status, as follows: patients with a TRV<2.5 m/s (group A), patients with a TRV≥2.5 m/s and a mPAP<25 mmHg (group B), and patients with a TRV≥2.5 m/s and a mPAP≥25 mmHg (group C). Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards modeling was used to compute hazard ratios (HR) along with their 95% confidence intervals (CI95).
Results
The 398 enrolled patients were followed-up for a mean time of 106±26 months (median 112 months, interquartile range 106-119). TRV was≥2.5 m/s in 109 patients (27.4%). RHC was performed in 98 of them and confirmed PH diagnosis (mPAP≥25 mmHg) in 24 (6%). Overall survival was significantly decreased in patients with a TRV≥2.5 m/s (groups B/C vs. A; HR=2.5 [CI95 1.3-4.7], p=0.006, Figure 1A). However, after accounting for mPAP level, no statistically significant difference was found between patients with a TRV<2.5 m/s and those with TRV≥2.5 m/s and mPAP<25 mmHg (group A vs. B, log-rank p=0.54), while patients with a TRV≥2.5 m/s and a confirmed diagnosis of PH by RHC (mPAP≥25 mmHg) had a significantly decreased survival in comparison with the two other groups (groups A/B vs. C, p<0.0001, Figure 1B), yielding the following HRs in Cox analysis: HR=1.0 (group A), HR=1.3 (group B, CI95 0.5-3.0, p=0.59] and HR=6.0 (group C, CI95 2.7-13.3, p<0.0001). At time of inclusion, patients with confirmed diagnosis of PH by RHC (group C) were older and characterized by lower 6-min walk distance, higher rate of leg ulcers, lower PaO2 and forced vital capacity, and higher levels of alkaline phosphatase, lactate deshydrogenase and γ-glutamyl transferase (all p<0.05). Clearance of creatinine was significantly lower in both groups with TRV≥2.5 m/s. All these parameters and systemic arterial pressures at time of inclusion were associated with a higher risk of mortality in univariate analysis.
Conclusion
While an isolated VRT≥2.5 m/s on transthoracic echocardiography was found to be a moderate prognostic factor for overall survival, our findings reveal highly contrasted outcomes depending on the mPAP values measured by RHC. Only the combination of a VRT≥2.5 m/s and a mPAP≥25 mmHg is associated with a worse prognosis, confirming that a RHC is mandatory in case of PH suspicion on transthoracic echocardiography in SCD patients.

Disclosures
Bartolucci: Addmedica: Research Funding; GBT: Membership on an entity's Board of Directors or advisory committees; Fondation Fabre: Research Funding; Novartis US: Membership on an entity's Board of Directors or advisory committees.