Triple combo therapy boosts heart, lung function in PAH study

Regimen found to ease disease severity in racially diverse group of patients

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Triple combination therapy — used to target multiple pathways — improves lung and heart function in pulmonary arterial hypertension (PAH) patients, according to real-world data from a racially diverse group.

The combo therapy resulted in a significant easing of disease severity, with no patient classified as high risk.

Being a woman was an independent predictor for risk reduction with the triple combo therapy, while Hispanic ethnicity was associated with lower likelihood of risk reduction.

“Our study confirms a sustained and long-term clinical and survival benefit with add-on sequential triple combination therapy in a racially diverse population,” researchers wrote in the study “Long-term impact of add-on sequential triple combination therapy in pulmonary arterial hypertension: real world experience,” which was published in the journal Therapeutic Advances in Respiratory Disease.

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Sequential triple combination therapy recommended for certain PAH patients

PAH is a form of pulmonary hypertension in which blood vessels in the lungs are narrowed. It can result in right heart failure, due to the excessive workload on the heart.

Several pathways contribute to disease onset and progression. Sequential triple combination therapy is recommended for PAH patients at intermediate-low risk at follow-up. However, data on its long-term efficacy are lacking.

To shed light on this, researchers at West Virginia University and New York University (NYU) conducted a study of a racially/ethnically diverse group of PAH patients receiving treatment with triple combination therapy.

Participants were followed at the NYU Langone Health Pulmonary Hypertension Center from January 2017 to July 2021. They were on a stable dual therapy regimen but started the triple therapy after failing to improve.

The most common dual combination therapy, used by 81.8%, included phosphodiesterase-5 inhibitors (PDE5i) or a soluble guanylate cyclase (sGC) stimulator — agents that induce blood vessel widening and relaxation — and an endothelin receptor antagonist (ERA).

Of 414 patients, 102 initiated the triple combo regimen. The final analysis included 55 patients with available data, who were a mean age of 57 years and 85.5% of them were women. The majority (41.8%) had idiopathic (no known cause) or inherited PAH, followed by connective tissue disease-associated PAH (30.9%).

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34.5% of patients who started triple combo therapy were considered high risk

Patients started the triple combination therapy after a median of 120 weeks (about 2.3 years) after diagnosis. About a third of them (34.5%) were deemed as high risk, as assessed by the REVEAL 2.0 score, and 76.4% were classified as functional class III by the World Health Organization. The higher the functional class, the more severe the symptoms.

The most common sequential triple combination therapy included PDE5i or sGC stimulator, an ERA, and Uptravi (selexipag) (43.6%), followed by a prostacyclin therapy (25.5%) given by parenteral (not via the digestive tract) administration.

Several parameters were assessed, including WHO functional class, the 6-minute walk test (6MWT, to assess exercise capacity), diffusing capacity for carbon monoxide (DLCO, a standard lung function parameter), pulmonary vascular resistance or the resistance of lung blood vessels to blood flow, and measures of heart function. The heart function measures included the size of the right ventricle and tricuspid annular planar systolic excursion (TAPSE), an imaging method to assess the health of the right ventricle, which is the part responsible for pumping blood to the lungs to pick up oxygen.

After a median of 68 weeks (about 1.3 years) of follow-up, results showed significant improvements in WHO functional class, DLCO, 6MWT, as well as a reduction in REVEAL 2.0 risk category. Up to 61.8% of participants achieved or maintained low-risk status compared to 38.2% at baseline, and no patient remained in the high-risk category.

Significantly lower pulmonary vascular resistance was seen in 28.6% of patients. Heart function also improved. Non-white patients experienced better heart function, as well as a lower REVEAL 2.0 risk category and improved 6MWT scores.

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Triple combo therapy generally well tolerated with some GI side effects

The triple therapy was generally well tolerated, but the regimen was associated with a significant increase in side effects, particularly those affecting the gastrointestinal tract.

A statistical analysis showed that being a woman was a strong predictor of lower risk. In contrast, lower odds of risk reduction was associated with Hispanic/Latino ethnicity, right atrial pressure (the blood pressure in the upper right chamber of the heart), and pericardial effusion, which is the buildup of fluid in the space around the heart.

Risk reduction was linked to significantly improved survival in the long term.

Overall, these findings support the long-term effectiveness of triple combo therapy. However, “since not all patients achieve therapeutic goal with the sequential triple drug regimen, there is a need for continuous and rigorous monitoring and, as needed, up-titration of therapy and/or transplant referral,” the researchers wrote, adding that “patients of Hispanic ethnicity have lower odds of risk reduction, and these findings need to be explored in larger studies.”

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