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Baseline and Follow-Up 6-Min Walk Distance and Brain Natriuretic Peptide Predict 2-Year Mortality in Pulmonary Arterial Hypertension
Study Questions:
What is the individual and additive ability of pretreatment and post-treatment 6-minute walk distance (6MWD) and B-type natriuretic peptide (BNP) to discriminate 2-year survival in patients with pulmonary arterial hypertension (PAH)?
Methods:
All patients were enrolled in one of two 12-week randomized, placebo-controlled clinical trials of ambrisentan. Each was placed on ambrisentan with blinded dosing during a 2-year follow-up (n = 370); 6MWD and BNP were assessed before and after 12 weeks of treatment. Receiver operating characteristic curve analyses were performed to identify optimal cutoffs that defined subgroups with a high 2-year mortality. Classification and regression tree analysis was used to determine the incremental prognostic value of combined assessments.
Results:
The mean age was about 52 years, 64% had idiopathic PAH, 32% PAH-connective tissue disease, and about 90% were World Health Organization (WHO) class II/III. Baseline mean (1-standard deviation) 6MWD was 348 m (85), and BNP was 138 pg/ml (range, 47-350). 6MWD at baseline and after 12 weeks of therapy were similarly discriminatory of 2-year survival (c-statistics = 0.77; 95% confidence interval [CI], 0.70-0.84 and 0.82; 95% CI, 0.75-0.88, respectively), whereas change in 6MWD from baseline to week 12 was not discriminating. The same observation was true of BNP at baseline and after 12 weeks of therapy (c-statistics = 0.68; 95% CI, 0.60-0.76 and 0.74; 95% CI, 0.66-0.82, respectively). A baseline 6MWD <250 m (or <300 m after 12 weeks of treatment) was associated with about a 50% risk of death at 2 years versus 8% risk of death for subjects above these cutoffs. A baseline BNP of >350 pg/ml or >330 pg/ml after 12 weeks of treatment was associated with a 25%-40% risk of death at 2 years versus a 10% risk of death for those below these cutoffs. After consideration of baseline 6MWD, there was no prognostic information added by the week 12 6MWD or BNP at either time point.
Conclusions:
6MWD and BNP values at baseline or week 12 identified a population with an elevated risk of death at 2 years. A repeat assessment of 6MWD or BNP after 12 weeks of ambrisentan therapy did not provide additional prognostic information beyond that obtained from baseline values.
Perspective:
Large registries have demonstrated that baseline 6MWD is an independent predictor of survival, and guidelines recommend the 6MWD to be a routine part of the baseline assessment used to determine treatment. In a meta-analysis of 22 trials involving 3,112 subjects in randomized trials, an improvement in 6MWD did not reflect a benefit in clinical outcomes. Considering that in placebo-controlled clinical trials the change in 6MWD is not a major determinant of treatment decisions, the clinical applicability of the on-trial finding to clinical practice is limited.
Keywords: Connective Tissue Diseases, Follow-Up Studies, World Health Organization, Ventricular Dysfunction, Right, Pyridazines, Treatment Outcome, Heart Diseases, Prognosis, Registries, Biomarkers, Heart Failure, Hypertension, Pulmonary, Confidence Intervals, ROC Curve, Phenylpropionates, Natriuretic Peptide, Brain
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