Grouped Measures of Clinical Worsening May Help Predict Outcomes in Children with PAH, Study Suggests

Ana Pena, PhD avatar

by Ana Pena, PhD |

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A combination of measures of clinical worsening may be meaningful in determining response to therapies in pediatric clinical trials, and a good gauge prognosis in children with pulmonary arterial hypertension (PAH), a registry-based study reports.

Disease worsening defined by the occurrence or progression of symptoms, particularly, was found to be a valid predictor of the need for a lung transplant and of death in these patients, the researchers wrote. With two other measures, it is useful for monitoring outcomes, assessing risk, and informing treatment decisions in clinical routine, the researchers wrote.

Their findings were reported in “Meaningful and feasible composite clinical worsening definitions in paediatric pulmonary arterial hypertension: An analysis of the TOPP registry,” published in the International Journal of Cardiology.

“As there are multiple similarities between pediatric and adult patients with PAH, diagnostic and therapeutic algorithms used in adult PAH have been adopted, with some adaptations, for disease management in children, based on small-scale studies and expert opinion,” the researchers said.

But important differences between pediatric and adult populations preclude use of the same measures for clinical worsening.

For example, the 6-minute walk distance test, which is widely used in adults to assess exercise capacity, is known to be unreliable in children (likely because of their developing gait); the right-sided heart catheterization, a gold standard for diagnosis and clinical follow-up in adults, is not supported as an efficacy measure in children because it’s an invasive procedure.

Therefore, a group of researchers explored if a composite measure, or a combination of outcomes, might better reflect clinical worsening (cCW) in children, a view that’s emerging in the field.

They looked at data from 255 children newly diagnosed with PAH (three months or less) and enrolled in the global TOPP registry which collected such data between Jan. 31, 2008, and Feb. 15, 2010. They evaluated the frequency of clinical worsening events using three different composite outcomes, and determined how valuable these measures were in predicting a lung transplant or death (disease prognosis) in a patient.

The three cCW outcomes combined different endpoints/events: all-cause death, PAH-related hospitalization, lung transplant, atrial septostomy (a procedure to reduce pressure in the right side of the heart), deterioriation by WHO functional class, intravenous or under the skin injections of prostanoids (e.g., epoprostenol, brand names Flolan, Veletri; and treprostinil, Remodulin, and others), syncope (fainting), and the occurrence or worsening of two or more symptoms of PAH.

cCW1 included the fewest endpoints (four), followed by cCW2 (seven endpoints) and cCW3, which combined all endpoints.

Data showed a first event of clinical worsening, from the ones specified, at a rate of 23.1 if defined by cCW1, 43.6 if using cCW2, and 46.3 if measured by cCW3 over 100 person-years.

Person-years is a term used to define the incidence or rate of an event. For instance, an even rate of one in 100 person-years means one event will happen to one person when following 100 people for one year.

PAH-related hospitalization was the most common first event reported among the newly diagnosed children.

Importantly, all composite definitions were associated with a higher risk of lung transplant or death, supporting their predictive strength for estimating patient outcomes.

Looking at each measure (trial endpoints) individually, those best associated with higher risks were WHO functional class deterioration, PAH-related hospitalization, and occurrence or worsening of at least two PAH symptoms.

“The results from this analysis of the TOPP registry suggest that different CW definitions could be used as primary endpoints in future pediatric PAH trials and prognostic studies,” the researchers wrote.

And they suggest that fewer pediatric patients are needed for valid trial outcomes than in adult trials.

“Indeed, the number of events according to the different definitions is high and the events occur early in the course of the disease,” they added. These two findings suggest that fewer pediatric patients “needed to be included in randomised control trials … compared with the event-driven trials in adult PAH.”

The study also supports that a definition of PAH worsening based on the occurrence or progression of symptoms “may be predictive” of the likelihood of death and a lung transplant in a patient, the team concluded, and “therefore could be used for prognostic studies and in clinical practice to identify patients at higher risk of disease progression and poorer outcomes.”

Measures based on syncope (fainting) were determined not to be of predictive value “in line with results of previous cohort studies.”

A Conversation With Rare Disease Advocates