Predicting Survival in Patients With Sickle Cell Disease and Pulmonary Hypertension

In an analysis of long-term data from a cohort study of adults with sickle cell disease (SCD), researchers confirmed that pulmonary hypertension (PH) is associated with a poor prognosis in this population. The study’s authors, led by Laurent Savale, MD, PhD, from Hôpitaux de Paris in France, also identified a “hyperhemolytic phenotype” of SCD associated with a higher risk of death.

Co-author Pablo Bartolucci, MD, PhD, from Henri Mondor Hospital in Creteil, France, presented findings from the prospective ETENDARD Evaluation of the Prevalence of Pulmonary Hypertension in Adult Patients With Sickle Cell Disease) study at the 2018 ASH Annual Meeting.

ETENDARD evaluated the prevalence of PH in 398 outpatients with SCD enrolled between February 2007 and March 2009 at referral centers in France. All patients were homozygous for hemoglobin S or had Sβ0 thalassemia.

In an earlier analysis, researchers estimated the prevalence of PH related to SCD to be 6 percent, and the risk for developing PH was greater in patients who had a tricuspid regurgitation velocity (TRV) ≥2.5 m/s and a mean pulmonary arterial pressure (mPAP) ≥25 mmHg (as measured by right-sided heart catheterization; RHC).

To determine the long-term prognostic value of TRV ≥2.5 m/s and the level of mPAP, the authors analyzed 10-year follow-up data from ETENDARD cohort. Per study protocol, participants underwent Doppler echocardiography to determine TRV; those with suspected PH (defined as TRV ≥2.5 m/s) then underwent RHC to determine mPAP. Patients were categorized according to their TRV/mPAP status:

  • group A (no PH): patients with a TRV <2.5 m/s
  • group B (precapillary PH): patients with a TRV ≥2.5 m/s and a mPAP <25 mmHg
  • group C (post-capillary PH and hyperkinetic state): patients with a TRV ≥2.5 m/s and a mPAP ≥25 mmHg

In this report, Dr. Savale reported long-term results from a median follow-up of 8.8 years (range not available).

A total of 109 patients (27.4%) had TRV ≥2.5 m/s. Ninety-eight of these patients had RHC performed, 24 of whom (6%) had a confirmed PH diagnosis (defined as a mPAP≥25 mmHg) – consistent with earlier research.

“While an isolated TRV ≥2.5 m/s on transthoracic echocardiography was found to be a moderate prognostic factor for overall survival,” the authors reported, “our findings reveal highly contrasted outcomes depending on the mPAP values measured by RHC.”

Overall survival was significantly lower in patients with a TRV ≥2.5 m/s (HR=2.5; 95% CI 1.3-4.7; p=0.006 for groups B and C vs. group A). After accounting for mPAP level, though, there was no statistically significant difference between patients with a TRV <2.5 m/s (group A) and those with TRV ≥2.5 m/s and mPAP <25 mmHg (group B; p=0.54).

Only the combination of TRV ≥2.5 m/s and a mPAP ≥25 mmHg (i.e., a confirmed diagnosis of PH) was associated with statistically significantly reductions in overall survival, compared with those in groups A and B:

  • group A: HR=1.0
  • group B: HR=1.3 (95% CI 0.5-3.0; p=0.59)
  • group C: HR=6.0 (95% CI 2.7-13.3; p<0.0001)

Also, in univariate and multivariate analysis, the authors found that the following factors were associated with a higher risk for death:

  • older age
  • lower hemoglobin levels
  • higher TRV
  • higher hemolysis rate
  • presence of chronic organ damage
  • higher arterial pressure
  • presence of PH
  • presence of ulcers (p values not available)

“Surprisingly, there was no difference in risk of death according to leukocyte count or percentage of HbF [in the univariate analysis],” Dr. Bartolucci noted. In the multivariate analysis, there also was no difference in death risk according to sex, history of veno-occlusive crises, or tobacco use.

Taking these data together, the authors created a “hyperhemolytic phenotype” of SCD: Patients with pre- and post-capillary PH, leg ulcers, chronic kidney disease, and higher systolic blood pressure have a poorer risk of survival.

Dr. Bartolucci noted that these results need to be replicated in other cohorts, and that future studies should focus on the role of transfusion in patients with higher-risk SCD, according to the factors identified here.

The authors report financial relationships with Novartis, Addmedica, and GBT.


Savale L, Loko G, Lionnet F, et al. Predictive factors for survival in sickle cell disease: a cohort study using Etendard data. Abstract #7. Presented at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.