Baseline and Follow-up 6-Min Walk Distance and Brain Natriuretic Peptide Predict 2-Year Mortality in Pulmonary Arterial Hypertension

doi:10.1378/chest.12-0270

Chest

Volume 143, Issue 2, February 2013, Pages 315-323

https://doi.org/10.1378/chest.12-0270 Get rights and content

Background

Six-minute walk distance (6MWD) and brain natriuretic peptide (BNP) levels at baseline and after initiation of treatment have been associated with survival in patients with pulmonary arterial hypertension. Our objective was to determine the individual and additive ability of pretreatment and posttreatment 6MWD and BNP to discriminate 2-year survival in patients with pulmonary arterial hypertension.

Methods

We included patients enrolled in two randomized clinical trials of ambrisentan who had 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

6MWD at baseline and after 12 weeks of therapy were similarly discriminatory of 2-year survival (c-statistics = 0.77 [95% 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). 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.

Section snippets

Materials and Methods

This study was approved by the Institutional Review Board of the University of Pennsylvania (approval No. 814307). Additional details of the methods and statistical analysis are provided in e-Appendix 1.

ARIES (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study)-1 and ARIES-2 were concurrent, phase 3, double-blind, placebo-controlled RCTs of ambrisentan for the treatment of PAH.⁸ Patients were randomized to placebo or

Results

There were 383 subjects in the study cohort (Fig 1). We excluded 13 who did not have 2-year survival status data from the primary analyses, leaving 370 subjects in the study sample for the 6MWD analysis. Thirty-seven additional subjects were excluded from the BNP analyses due to missing baseline BNP values, leaving 333 in the study sample. Baseline demographics of the study samples and those excluded are presented in Table 1, Table 2, for descriptive purposes only. Most patients had idiopathic

Discussion

In this study, we assessed the ability of baseline and 12-week 6MWD and BNP levels to discriminate PAH patients with a high vs low risk of death at 2 years after treatment with ambrisentan. Both 6MWD at baseline and at 12 weeks after treatment displayed moderately strong predictive ability for discriminating patients at high and low risks of death at 2 years. Similar findings were observed for baseline and 12-week BNP levels, although these were somewhat weaker predictors. A baseline 6MWD < 250

Acknowledgments

Author contributions: Drs Fritz and Kawut guarantee the integrity of the study.

Dr Fritz: contributed to study conception and design, data analysis and interpretation, as well as article drafting and revision, and gave final approval.

Ms Blair: contributed to data analysis and interpretation as well as article revision and gave final approval.

Dr Oudiz: contributed to data analysis and interpretation as well as article revision and gave final approval.

Dr Dufton: contributed to data analysis and

References (22)

RJ Raymond et al.
Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension
J Am Coll Cardiol
(2002)
SM Kawut et al.
Six-minute walk distance and B-type natriuretic peptide as discriminators of survival in patients with pulmonary arterial hypertension
Chest
(2009)
RJ Oudiz et al.
Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension
J Am Coll Cardiol
(2009)
SM Kawut et al.
New predictors of outcome in idiopathic pulmonary arterial hypertension
Am J Cardiol
(2005)
MC van de Veerdonk et al.
Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy
J Am Coll Cardiol
(2011)
DB Badesch et al.
Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry
Chest
(2010)
RL Benza et al.
The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension
Chest
(2012)
A Fijalkowska et al.
Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension
Chest
(2006)
RL Benza et al.
Prognostic factors associated with increased survival in patients with pulmonary arterial hypertension treated with subcutaneous treprostinil in randomized, placebo-controlled trials
J Heart Lung Transplant
(2011)
VV McLaughlin et al.
Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial
J Am Coll Cardiol
(2010)

NB Gabler et al.

Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension

Chest

(2012)

Cited by (91)

The evolving landscape of pulmonary arterial hypertension clinical trials
2022, The Lancet
Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.
Prognostic value of improvement endpoints in pulmonary arterial hypertension trials: A COMPERA analysis
2022, Journal of Heart and Lung Transplantation
The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated.
Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses.
All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools.
While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials.
Prognostic Value of Right Ventricular Two-Dimensional and Three-Dimensional Speckle-Tracking Strain in Pulmonary Arterial Hypertension: Superiority of Longitudinal Strain over Circumferential and Radial Strain
2020, Journal of the American Society of Echocardiography
Right ventricular (RV) dysfunction is a predictor of adverse outcomes in patients with pulmonary arterial hypertension (PAH). Three-dimensional (3D) speckle-tracking echocardiography (STE) has been increasingly used to quantify RV function. However, the strain parameters evaluated by two-dimensional (2D) STE and 3D STE, which provide the most valuable clinical information, remain unknown. The purpose of our study was to investigate whether RV longitudinal strain (LS) provided a superior estimation of RV systolic performance and prognostic information compared with other strain vectors.
We prospectively studied 54 treatment-naïve patients with PAH and 35 normal controls. Pulmonary artery systolic pressure classified patients with PAH into three subgroups. Patients with PAH underwent echocardiography, cardiac magnetic resonance (CMR) imaging, 6-minute walking tests, and right-sided cardiac catheterization before and six months after vasodilator therapy. The 2D LS, 3D LS, circumferential strain (CS), and radial strain (RS) of RV free wall were calculated by 2D and 3D STE. RV ejection fraction (RVEF) was obtained from CMR. The patients were followed for a predefined endpoint of PAH-related hospitalization and death.
Our findings revealed that 2D and 3D LS showed significant reduction in mild PAH patients, whereas CS and RS were decreased in moderate and severe PAH patients. Right ventricular 3D LS had a similar correlation with CMR RVEF and hemodynamic parameters as 2D LS and the other strain vectors. The 2D and 3D LS improved 6 months after vasodilator therapy (P < .001 for both). After a median follow-up of 28 months, 20 patients had endpoint events. Receiver operating characteristic curve analysis demonstrated that RV 3D LS displayed a similar diagnostic performance for detecting adverse cardiac events as 2D LS (area under the curve: 0.84 vs 0.76, P = .11). Separate multivariable Cox analysis showed that RV 2D LS (hazard ratio [HR] = 1.19; 95% CI, 1.03～1.45; P = .01) and 3D LS (HR = 1.28; 95% CI, 1.08～1.52; P = .005) were significant predictors of adverse outcomes.
Patients with PAH show reduced RV strain. Two-dimensional and 3D LS can track clinical improvement following vasodilator therapy and provide valuable prognostic information.
Risk stratification strategy and assessment of disease progression in patients with pulmonary arterial hypertension: Updated Recommendations from the Cologne Consensus Conference 2018
2018, International Journal of Cardiology
Citation Excerpt :
There is still no specific marker for PAH or pulmonary vascular remodelling, although a wide variety of biomarkers have been explored in the field. These can be grouped into markers of vascular dysfunction [asymmetric dimethylarginine (ADMA), endothelin-1, angiopoeitins, von Willebrand factor] [39–44], markers of inflammation (C-reactive protein, interleukin 6, chemokines) [45–48], markers of myocardial stress (atrial natriuretic peptide, brain natriuretic peptide (BNP)/NT-proBNP, troponins) [4,30,49–52], markers of low CO and/or tissue hypoxia [pCO2, uric acid, growth differentiation factor 15 (GDF15), osteopontin] [53–56] and markers of secondary organ damage (creatinine, bilirubin) [4,52]. This list is constantly growing, but so far BNP and NT-proBNP remain the only biomarkers that are widely used in the routine practice of PH centres as well as in clinical trials.
In the summer of 2016, delegates from the German Respiratory Society, the German Society of Cardiology and the German Society of Pediatric Cardiology met in Cologne, Germany, to define consensus-based practice recommendations for the management of patients with pulmonary arterial hypertension (PAH). These recommendations were built on the 2015 European Pulmonary Hypertension guidelines and included new evidence, where available, and were last updated in the spring of 2018. This article focusses on the proposed risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH), covering 3 parts: In part 1, methods and markers that are recommended to assess severity and progression of PAH are discussed and commented. These updated comments incorporate most recent data as well as challenges arising from the variability of phenotypes of PAH patients with increasing cardiopulmonary comorbidities. In part 2, the proposed ESC/ERS risk stratification strategy is discussed, together with a review of the recent validation studies from different European registries. Finally, in part 3, the working group of the Cologne Consensus Conference provides recommendations on how risk assessment may be implemented in routine clinical practice and may serve clinical decision making.
Stress hyperglycemia is associated with poor outcome in critically ill patients with pulmonary hypertension
2024, Frontiers in Endocrinology
Risk Stratification of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (Ssc-Pah) Using the Pharos Registry
2023, SSRN

View all citing articles on Scopus

For editorial comment see page 285

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Funding/Support: This work was supported by the National Institutes of Health [K24 HL103844 to S. M. K.].

View full text

Chest

Original ResearchPulmonary Vascular DiseaseBaseline and Follow-up 6-Min Walk Distance and Brain Natriuretic Peptide Predict 2-Year Mortality in Pulmonary Arterial Hypertension

Background

Methods

Results

Conclusions

Section snippets

Materials and Methods

Results

Discussion

Acknowledgments

J Am Coll Cardiol

Chest

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

Chest

Chest

Chest

J Heart Lung Transplant

J Am Coll Cardiol

Chest

Original Research
Pulmonary Vascular Disease
Baseline and Follow-up 6-Min Walk Distance and Brain Natriuretic Peptide Predict 2-Year Mortality in Pulmonary Arterial Hypertension