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Original Research: Pulmonary Vascular Disease |

Evaluation of the Predictive Value of a Clinical Worsening Definition Using 2-Year Outcomes in Patients With Pulmonary Arterial HypertensionClinical Worsening as Meaningful Prognostic Tool: A REVEAL Registry Analysis

Adaani E. Frost, MD, FCCP; David B. Badesch, MD, FCCP; Dave P. Miller, MS; Raymond L. Benza, MD; Leslie A. Meltzer, PhD; Michael D. McGoon, MD, FCCP
Author and Funding Information

From the Baylor College of Medicine (Dr Frost), Houston, TX; University of Colorado Health Sciences Center (Dr Badesch), Denver, CO; ICON Late Phase & Outcomes Research (Mr Miller), San Francisco, CA; Allegheny General Hospital (Dr Benza), Pittsburgh, PA; Actelion Pharmaceuticals US, Inc (Dr Meltzer), South San Francisco, CA; and Mayo Clinic (Dr McGoon), Rochester, MN.

Correspondence to: Adaani E. Frost, MD, FCCP, Baylor College of Medicine, MS 621, 6620 Main St, Houston, TX 77030; e-mail: frost@bcm.tmc.edu


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.


Chest. 2013;144(5):1521-1529. doi:10.1378/chest.12-3023
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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

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