Combining Endpoints May Better Predict PAH Survival Outcomes
Combining measures of symptom severity, physical function, and heart health can help predict survival outcomes in pulmonary arterial hypertension (PAH), according to a new study.
It’s necessary to have good endpoints (or goals) to test whether the investigational therapy is working when conducting clinical trials in PAH or any other condition. Ideally, this involves objectively measurable markers that are relatively short-term and can provide reliable information about long-term outcomes, such as survival.
Historically, most PAH clinical trials have evaluated the distance participants can walk in six minutes (6MWD), a common assessment of physical function in ambulatory people, as a main endpoint. However, recent research has suggested that 6MWD is not very useful for predicting long-term outcomes.
“To be useful as outcome measures in PAH trials, endpoints need to be clinically relevant and must be accepted by key stakeholders including patients, physicians, regulatory agencies, and payors,” the researchers wrote.
“Change in 6MWD is still accepted as primary outcome measure by regulatory agencies as a measure of functional capacity … However, given the lack of association between 6MWD improvement and survival, change in 6MWD alone is viewed with skepticism by patients, physicians, and payors,” they said.
Other endpoints that may be useful for PAH include blood levels of NT-proBNP, a marker of heart damage, or functional class, essentially a rating of symptom severity. Combining these markers also may be useful. Their utility, alone or in concert, remains incompletely validated.
A team of scientists in Europe analyzed data from the COMPERA database Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (NCT01347216), which tracks outcomes for newly diagnosed PAH patients in several European countries.
The analysis included data for 596 people with PAH. Two-thirds of these patients were female, with a mean age of 61. All of them had completed at least one initial study visit and an additional follow-up visit several months later.
The median observation time after the first follow-up visit was three years. Estimated survival rates were 95% after one year, 76.3% after three years, and 65.5% after five years.
From the study start to the first follow-up, about one in three patients showed an improvement in functional class and survival outcomes were significantly better in these patients. Changes in 6MWD were not significantly associated with long-term survival, however.
Reductions in NT-proBNP levels were not associated with survival, but greater relative changes in NT-proBNP levels (measured as a percent of study start values) were.
“Our study showed that improvements in [functional class] were associated with improved consecutive survival, while improvements in NT-proBNP had relatively little and improvements in 6MWD no predictive value,” the researchers concluded.
The team then analyzed different combinations of these endpoints, including combinations used in the clinical trials REPLACE (NCT02891850) and PULSAR (NCT03496207) and other risk stratification tools, such as the ESC/ERS 3-strata model. Results broadly showed that patients who met the combined endpoints had significantly better survival outcomes.
“Our data suggest that improvements in multicomponent endpoints and established risk stratification models predict survival. These tools should be further investigated as outcome measures in PAH trials to determine whether they may eventually become acceptable surrogate endpoints in the future,” the researchers wrote.