Predictors of Six-Minute Walk Distance In Adults with Sickle Cell Anemia In the Walk-PHaSST Study

Many patients with sickle cell disease have decreased functional capacity as measured by the six-minute walk (6MW) test compared to controls; however, there is considerable variability in exercise performance among the patients themselves[1, 2]. To date, the 6MW test has not been evaluated in a large cohort of adult sickle cell anemia patients.

Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) includes an on-going observational study of sickle cell disease patients at nine United States Centers and one United Kingdom Center. In the screening phase of the study, patients had clinical evaluation, echocardiography and 6MW testing performed. Of 720 patients screened, 483 had hemoglobin SS phenotype. To investigate potential prognostic predictors for decreased exercise capacity, we analyzed, among patients with hemoglobin SS, the relationship of baseline clinical characteristics with 6MW distance (6MWD). The Doppler-echocardiographically measured tricuspid regurgitation velocity (TRV) estimates right ventricular systolic pressure, and left ventricular lateral wall E/Ea ratio estimates left ventricular filling pressure. Walk-PHaSST prospectively defined 3 patient cohorts based on screening TRV: < 2.7 m/sec, 2.7–2.9 m/sec and ≥3.0 m/sec.

Of 483 hemoglobin SS patients, the median age was 35 years (range 12 to 69 years) and the gender split was 250 females to 233 males. The 6MWD was measured in 475 patients, TRV was measured in 453, LV lateral wall E/Ea was measured in 436 and hemolytic component was calculated in 406. The median 6MWD was 438 m (inter-quartile range of 383–504 m and overall range of 123–711 m). TRV was 2.7–2.9 m/sec in 22% and ≥3.0 m/sec in 17%.

By linear regression, female gender was independently associated with an estimated 44 m decrease in 6MWD (95% CI of 27–61 m; P <0.0005), a 10-year increase of age with a 13 m decrease in 6MWD (95% CI of 5–20 m); P = 0.001), a log increase in LV lateral wall E/Ea ratio with a 39 m decrease in 6MWD (95% CI of 13–66 m; P = 0.004) and each higher category of TRV with a 17 m decrease in 6MWD (95% CI of 4–29 m; P = 0.007).

In a pathway analysis, higher TRV and LV lateral wall E/Ea ratios were directly associated with decreased 6MWD. Elevated creatinine, higher hemolytic component and degree of anemia were not associated with 6MWD. However, elevated creatinine was directly associated with both higher TRV and lateral wall E/Ea ratios, and elevated hemolytic component was directly associated with higher TRV.

In this prospective multicenter, international study of patients with sickle cell anemia, we found higher estimated: 1) right ventricular systolic pressure, and 2) left ventricular filling pressure (as determined by Doppler-echocardiography) to be independently associated with decreased functional capacity, after adjusting for gender and age. These data suggest that cardiac dysfunction may contribute to impaired exercise capacity in sickle cell anemia. These studies suggest that the 6MW test may be an appropriate endpoint for controlled studies directed at improving cardiac function in patients with sickle cell anemia.

1. Gladwin, M.T., et al., Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med, 2004. 350(9): p. 886–95.

2. Minniti, C.P., et al., Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica, 2009. 94(3): p. 340–7.

Barst:Pfizer: Consultancy, Research Funding. Kato:Ikaria-INO Therapeutics: Research Funding, Research Funding as part of a CRADA (Cooperative Research and Development Agreement with NIH). Hassell:Novartis: Research Funding. Badesch:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gladwin:Ikaria-INO Therapeutics: Research Funding, With NIH through a Cooperative Research and Development Agreement.