Non-Cardiopulmonary Factors Affecting the Six-Minute Walk Distance in Patients with Sickle Cell Disease: Results From the Walk-PHaSST Study

The six-minute walk (6MW) test is frequently used to assess exercise capacity. Patients with sickle cell disease (SCD) can have decreased 6MW distance (6MWD) compared to controls. The 6MWD in conjunction with the TR-jet velocity (TRV) and NT-proBNP have recently been proposed to have a greater predictive value for screening SCD patients suspected of having pulmonary hypertension (PH) than TRV alone. (Parent et al, NEJM, 365; 1, 2011 365 (1):44–53). The American Thoracic Society guidelines recommend caution in controlling for sources of variability in the 6MWD (Am J Respir Crit Care Med 166. 111–117, 2002). Age and height are known confounders of the 6MWD. However, non-cardiopulmonary factors including skeletal-mechanics and pain may also impact the 6MWD.

This study explores whether non-cardiopulmonary factors affect the 6MWD in SCD patients.

We analyzed data from subjects screened for the walk-PHaSST trial. Walk-PHaSST was a multi-center, placebo-controlled, double-blind, 16-week trial evaluating the safety and efficacy of oral sildenafil for the treatment of Doppler-defined PH (TRV '2.7m/s) in subjects with SCD aged >12 years. The primary endpoint in the trial was change in 6MWD. During screening, subjects were evaluated by self-reported medical history, physical examination, blood sampling, echocardiography and 6MWD. Univariate and multivariable linear regression was performed. A two sided p value <0.05 was considered significant.

Of the 673 subjects screened, 671 had a 6MW test. The median (inter-quartile range) of 6MWD was 438m (503 – 381m = 122 m).

On univariate analysis, there was no statistically significant effect of the SCD genotype on the 6MWD (p=0.26). Further, when combining the severe genotypes (HbSS and HbSβ⁰ thalassemia) vs the less severe genotypes, there was no significant difference in the 6MWD (p=0.22).

By multivariable linear regression (Table 1), after adjusting for age, gender and TRV, the presence of the following (self-reported by subjects) were independently associated with an estimated decrease in the 6MWD: a) chronic pain (n = 260/671, 38.9%) by 24.3m (95% CI: 9.1–39.4m, p-value <0.01), b) history of avascular necrosis (AVN) of the hip (N =127/671, 18.9%) by 27.8m (95% CI: 9.2–46.4m, p-value <0.01), and c) osteopenia (N = 46/671,6.9% ) by 31.2m (95% CI: 2.7.-59.6m, p-value <0.05) There were no significant two-way interactions between chronic pain, AVN of the hip and/or osteopenia. History of leg ulcers, osteomyelitis and rheumatoid arthritis were not significant predictors of the 6MWD.

In this multi-center study of patients with SCD, history of self-reported: 1) chronic pain 2) AVN of the hip and 3) osteopenia were independently associated with decreased functional capacity (as assessed by the 6MW test), after adjusting for age, gender, and TRV.

While the 6MWD in patients with SCD is significantly related to cardiac function (i.e., PH and LV diastolic dysfunction), the potential effects of pain, osteonecrosis and osteopenia on 6MWD suggest that if using the 6MW test as the primary endpoint in future trials, one should consider documentation of the presence of these factors and use a stratified randomization based on a composite of these non-cardiopulmonary variables.

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