Should the Walk Test Be Used as a Surrogate Marker for CV Hemodynamics in SSc-PAH?

TOPIC SERIES: CVD PREVENTION IN RHEUMATIC DISEASE

The 6 minute walk distance (6MWD) test may not be an accurate surrogate indicator of systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH) treatment outcomes, and changes in cardiac hemodynamics in response to treatment may not be reliably estimated using interval changes in repeat 6MWD testing, new data indicate. Though the 6MWD has long been used as a proxy marker of cardiovascular hemodynamics and to predict pulmonary arterial hypertension (PAH) outcomes in SSc, no rigorous trial evaluating its validity as a predictor of outcomes had been conducted.

A clinical trial was recently performed to address this gap in knowledge by systematically assessing the relationship between right heart catheterization (RHC) parameters and the 6MWD, determining whether interval changes in 6MWD from baseline to follow-up were associated with hemodynamics in patients with SSc-PAH who did not have extensive interstitial lung disease (ILD).

“No work so far has ever quantified the correlation between the 6MWD and the gold standard RHC in SSc-PAH, a crucial requirement for its validation as a surrogate marker of hemodynamics severity and outcome according to the Outcome Measures in Rheumatology (OMERACT) filter,” the authors stated.

Researchers identified patients with SSc-PAH without extensive ILD and separated them into 2 distinct, independent cohorts. In the first cohort, the French Cohort, 83 patients with precapillary PAH and diagnosis of SSc according to the American College of Rheumatology 1980 criteria, were identified from the French national PAH network. These patients were not receiving pharmacotherapy for PAH at time of inclusion into the cohort.

In the second cohort, the US Food and Drug Administration (FDA) cohort, 332 patients with clinician-determined SSc with no extensive ILD and resting RHC-confirmed precapillary PAH were identified from several phase 3 randomized controlled trials submitted to the FDA in the drug approval process.

Patients had baseline demographic and clinical information recorded, including body mass index, disease duration, New York Heart Association (NYHA) functional class, serologic status, and current SSc-related medication. Per the protocols of the American Thoracic Society, the patients were asked to complete the 6MWD. Total 6MWD values, modified Borg scores, peripheral oxygen saturation, and heart rates were recorded prior and just after the test. Standard pulmonary function testing, arterial blood gasses, and transthoracic echocardiograms were also performed.

Resting RHC was performed within 2 days of administering the 6MWD. The following parameters were recorded: systolic, diastolic and mean pulmonary arterial pressures, pulmonary capillary wedge pressure, cardiac output (CO) and index, mean right atrial pressure, pulmonary vascular resistance and total pulmonary resistance, stroke volume, pulmonary arterial pulse pressure, pulmonary arterial capacitance, and right ventricular stroke work index.

PAH-specific medications, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, or prostacyclin analogues were initiated after baseline assessment at the discretion of the treating clinician. After a time period of at least 3 months after baseline assessment, follow-up testing was performed including repeat 6MWD and resting RHC.

Researchers found that after multivariate analysis, baseline 6MWD was independently associated with baseline CO (R²=0.19, P= .001) and New York Heart Association class (R²=0.10, P= .001) in the French cohort. This same correlation, albeit weaker, was also found in the FDA sample (R²=0.04, P= .001). Furthermore, no association between interval differences in 6MWD and RHC-determined hemodynamic variables were found in patients after receiving PAH-specific treatments.

“Our results suggest that: (1) absolute values of 6MWD are correlated with hemodynamic parameters, especially CO which is independently associated with baseline 6MWD in both cohorts; (2) CO explains only a small fraction of the variance of 6MWD in both cohorts (between 4% and 19%), highlighting the importance of extra hemodynamic factors in this test; (3) changes in the 6MWD between baseline and follow-up do not accurately reflect modifications of hemodynamics in treated patients,” the authors stated.

Summary and Clinical Applicability

This data indicates that interval measurements of 6MWD may not be a reliable or accurate surrogate measure of changes in hemodynamics after PAH treatment in patients with SSc-ILD with no severe ILD.

Reference

1. Sanges S, Launay D, Rhee RL, et al. A prospective study of the 6 min walk test as a surrogate marker for haemodynamics in two independent cohorts of treatment-naïve systemic sclerosis-associated pulmonary arterial hypertension. Ann Rheum Dis. 2016;75(8):1457-65.