Chest
Volume 144, Issue 5, November 2013, Pages 1521-1529
Journal home page for Chest

Original Research
Pulmonary Vascular Disease
Evaluation of the Predictive Value of a Clinical Worsening Definition Using 2-Year Outcomes in Patients With Pulmonary Arterial Hypertension: A REVEAL Registry Analysis

https://doi.org/10.1378/chest.12-3023Get rights and content

Background

Time to clinical worsening has been proposed as a primary end point in clinical trials of pulmonary arterial hypertension (PAH); however, neither standardized nor validated definitions of clinical worsening across PAH trials exist. This study aims to evaluate a proposed definition of clinical worsening within a large prospective, observational registry of patients with PAH with respect to its value as a predictor of proximate (within 1 year) risk for subsequent major events (ie, death, transplantation, or atrial septostomy).

Methods

We assessed overall 2-year survival and survival free from major events to determine the relationship between clinical worsening and major events among adults with hemodynamically defined PAH (N = 3,001). Freedom from clinical worsening was defined as freedom from worsening functional class (FC), a ≥ 15% reduction in 6-min walk distance (6MWD), all-cause hospitalization, or the introduction of parenteral prostacyclin analog therapy.

Results

In the 2 years of follow-up, 583 patients died. Four hundred twenty-six died after a documented clinical worsening event, including FC worsening (n = 128), a ≥ 15% reduction in 6MWD (n = 118), all-cause hospitalization (n = 370), or introduction of a prostacyclin analog (n = 91). Patients who experienced clinical worsening had significantly poorer subsequent 1-year survival postworsening than patients who did not worsen (P < .001).

Conclusions

Clinical worsening was highly predictive of subsequent proximate mortality in this analysis from an observational study. These results validate the use of clinical worsening as a meaningful prognostic tool in clinical practice and as a primary end point in clinical trial design.

Trial registry

ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov

Section snippets

Study Population

The design and baseline characteristics of patients enrolled in the REVEAL Registry have been previously described.7, 8 The REVEAL Registry is a large, multicenter, observational, US-based study that provides current information about demographics, disease progression, and management of patients with confirmed group 1 pulmonary hypertension (ie, PAH) and represents a cohort of patients similar to those seen in routine clinical practice. Patients are followed for a minimum of 5 years from the

Patient Characteristics

At the data collection end point on September 15, 2011, 3,001 REVEAL Registry patients met the analysis criteria of age > 18 years at the time of diagnosis and PCWP ≤ 15 mm Hg (Fig 1). Of those patients, 839 were newly diagnosed (diagnostic RHC < 3 months before enrollment). Patient characteristics at baseline and in the first year of follow-up are summarized in Table 1. Age and sex were similar between patients who clinically worsened in the first year of follow-up (n = 1,340) and patients who

Discussion

Several registries and open-label, long-term extension studies of prior placebo-controlled randomized clinical trials have assessed both survival and predictors of survival. These published data demonstrate that overall survival in the contemporary treatment era is improved compared with survival data from the original National Institutes of Health registry.11

One-year survival in patients with PAH (idiopathic PAH and associated PAH) varies from as high as 96%12 to 79%.13 Contemporary 1-year

Acknowledgments

Author contributions: Dr Frost had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Frost: contributed to the study design; data collection, analysis, and interpretation; and drafting, critical review, and final approval of the manuscript.

Dr Badesch: contributed to the study design; data collection, analysis, and interpretation; and drafting, critical review, and final approval of the manuscript.

Mr Miller:

References (26)

  • O Sitbon et al.

    Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival

    J Am Coll Cardiol

    (2002)
  • N Galiè et al.

    Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)

    Eur Heart J

    (2009)
  • N Galiè et al.

    Clinical worsening in trials of pulmonary arterial hypertension: results and implications

    Curr Opin Pulm Med

    (2010)
  • Cited by (69)

    • Perioperative Right Ventricular Dysfunction: Analysis of Outcomes

      2022, Journal of Cardiothoracic and Vascular Anesthesia
    • Cardiac-MRI Predicts Clinical Worsening and Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis

      2021, JACC: Cardiovascular Imaging
      Citation Excerpt :

      Clinical worsening as a composite endpoint has been shown to predict mortality (34) and has established itself as a primary efficacy endpoint in trials of PAH therapies (7,35). Although heart failure and all-cause mortality are included in all PAH trials using a composite clinical worsening endpoint, these trials vary in their inclusion and definition of progression markers, such as change in exercise tolerance or functional capacity (36), and they may use different thresholds to define a meaningful change (37). Nonetheless, study designs using time to clinical worsening have been increasingly adopted to evaluate PAH therapies.

    View all citing articles on Scopus

    Funding/Support: Preparation of this manuscript was supported by Actelion Pharmaceuticals US, Inc. Funding and support for the REVEAL Registry was provided by CoTherix, Inc, and its affiliate Actelion Pharmaceuticals US, Inc.

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

    View full text