Abstract
Introduction: Dyspnea and reduced exercise capacity are common in adults with sickle cell disease (SCD); the etiology is often multi-factorial. Six-minute walk testing (6MWT) is easy to perform and allows for assessment of exercise capacity and ambulatory oximetry. We hypothesized that patients with SCD and end organ dysfunction will have lower 6MWT distances and higher frequency of oxygen desaturations than those without end organ dysfunction. We used the baseline clinical data from the STERIO-SCD prospective, randomized placebo-controlled Phase 1-2 clinical trial of riociguat for treatment of high-risk patients with SCD to investigate this hypothesis.
Methods: Data were obtained as part of the multi-center STERIO-SCD clinical trial. Eligible patients were 18 years or older with SCD confirmed by hemoglobin (Hb) electrophoresis or high-performance liquid chromatography fractionation (all SCD genotypes), and at least one of the following high-risk criteria (HRC): 1) elevated systolic blood pressure (SBP) > 130 mmHg on at least two occasions, 2) an elevated tricuspid regurgitant jet velocity (TRV) > 2.9 m/s, or 3) proteinuria. 6MWT with oximetry on room air was performed utilizing standard protocols. In this descriptive analysis, we characterized baseline clinical values in the cohort by computing means and standard deviations or counts and proportions for continuous and categorical variables, respectively. These summary statistics were computed for the full cohort and separately for patient subgroups defined by the number of HRC each subject met.
Results: One hundred and fourteen patients were enrolled in STERIO-SCD and had at least one HRC; the mean age was 43.1 + 12.0 years, 51.8% were female and 71.1% had HbSS disease. The mean Hb for the cohort was 9.2 + 1.9 g/dl; 49.1% had elevated SBP > 130 mmHg on at least two occasions, 15.8% had an elevated TRV and 72.8% had proteinuria. Seventy-five (65.8%) had one HRC, 35 (30.7%) had two and 4 (3.5%) had three. The overall cohort had a mean baseline 6MWT distance of 396.6 + 145.3 m, which was reduced compared to the non-SCD population (normal 400-700 m depending on age, sex and height). Larger number of HRC criteria met was descriptively associated with shorter 6MWT distance and lower post-6MWT oxygen saturations; 6MWT distance was 416.7 + 158.6 m for those with one HRC, 359.8 + 92.6 m for those with two HRC, and 328.0 + 197.1 m for those with three HRC. Post-6MWT oxygen saturations were 96.6 + 3.5% in those with one HRC, 96.5 + 3.7% for those with two HRC, and 88.0 + 11.1% for those with three HRC.Conclusion: Patients with SCD and systemic hypertension, an elevated TRV and/or proteinuria reflective of end-organ damage exhibit lower exercise capacity and ambulatory oxygen saturations. Reduced exercise capacity and oxygen desaturation are associated with a greater degree of organ dysfunction. This suggests that end-organ disease plays a role in limitations of the observed reduced functional capacity in patients with SCD and that 6MWT may be a way of identifying higher risk patients who require further evaluation for evidence of cardiopulmonary and renal disease.
