Levels of NT-proBNP can predict long-term outcomes and response to treatment with Uptravi (selexipag) in patients with pulmonary arterial hypertension (PAH), a post-hoc analysis of the Phase 3 GRIPHON trial shows.
The study, “Association of NT-proBNP and Long-Term Outcome in Patients with Pulmonary Arterial Hypertension: Insights from the Phase III GRIPHON Study,” was published in the journal Circulation.
PAH is characterised by increased blood pressure on the arteries that pump blood from the heart into the lungs. These blood vessels become narrow, making the heart work harder to pump blood to the lungs, which can lead to serious cardiac complications.
NT-proBNP is a peptide secreted by heart cells called cardiomyoctes upon damage, and is currently used as a non-invasive biomarker for heart right side dysfunction. Data from the REVEAL registry suggests that NT-proBNP levels of 340 nanograms per liter (ng/L) of blood significantly predict PAH patient’s survival up to five years.
However, further studies are necessary to confirm the levels at which NT-proBNP can predict PAH outcomes.
The Phase 3 GRIPHON study (NCT01106014) was a worldwide, double-blind, randomized trial that assessed the clinical safety and efficacy of Uptravi (market by Actelion Pharmaceuticals) for the treatment of PAH compared with a placebo group.
Uptravi is a medication approved by the U.S. Food and Drug Administration (FDA) to delay disease progression in patients with PAH.
The GRIPHON trial included an exploratory objective that assessed changes in the level of NT-proBNP, which were measured at regular intervals during the trial. The researchers took advantage of these data to determine the prognostic value of NT-proBNP thresholds.
The team evaluated a total of 1,142 patients from the GRIPHON study, which were divided into three subgroups according to NT-proBNP levels — low, medium, and high NT-proBNP — using two independent thresholds, the baseline tertiles and the 2015 ESC/ERS guideline cut-offs.
According to the baseline tertiles, low NT-proBNP corresponded to values below 271 ng/L; medium levels were considered between 271 and 1165 ng/L; and high was any level above 1165 ng/L. Using the 2015 ESC/ERS guideline cut-offs, low was a level below 300 ng/L; medium was between 300 and 1400 ng/L; and high was above 1400 ng/L.
The main analyses were based on baseline tertile thresholds, with 381 patients classified as having low levels, 380 as having medium levels, and 381 as having high NT-proBNP levels.
The levels of NT-proBNP were measured at weeks four, eight, 16, and 26, and at six-month intervals thereafter.
Overall, the results showed that Uptravi-treated patients (17.4%) experienced improvements in NT-proBNP levels (meaning a reduction in levels) more frequently compared with placebo controls (8.3%).
For placebo-treated patients, the researchers saw that the mortality rate increased according to NT-proBNP levels, specifically 21.5% in the low NT-proBNP group, 43.5% in the medium level group, and up to 57.8% in the high NT-proBNP group.
A similar pattern was seen in the Uptravi-treated patients, where the mortality rate increased from the low NT-proBNP (12.3%) to the medium NT-proBNP (22.4%) to the high NT-proBNP (47.5%) subgroups.
Data analysis showed that the risk of death was 90% lower in placebo-treated patients with low NT-proBNP levels and 56% lower in the medium NT-proBNP level, compared with patients with high NT-proBNP levels. In the Uptravi-treated patients, the risk was 92% lower in the low group, and 83% lower in the medium group.
Researchers saw similar results when setting the thresholds according to the 2015 ESC/ERS guidelines.
The analysis also showed that treatment with Uptravi reduced the risk of disease progression and mortality across all three NT-proBNP subgroups, but the treatment benefits were more evident in the low and medium NT-proBNP subgroups. This suggests that earlier Uptravi treatment may be of greater benefit.
A higher proportion of patients in the Uptravi group stopped treatment before the trial’s end due to side effects compared with the placebo group: 11.3% of treated patients versus 6.5% of the placebo controls in the low NT-proBNP group; 15.7% of treated patients versus 6% of the placebo controls in the medium group; and 16.4% of the treated patients versus 8.8% of the placebo controls in the high group.
Uptravi was overall well-tolerated, independent of NT-proBNP levels at the start of the trial.
The results indicate that low levels of NT-proBNP, and the maintenance of a low level, is important in the treatment of PAH.
Overall, “in our analyses, NT-proBNP category at baseline and at any time during follow-up, irrespective of whether the categories were based on the ESC/ERS guideline thresholds or baseline tertiles, was shown to be highly prognostic for long-term outcomes and can be used to predict response to selexipag treatment,” the team concluded.
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