Combination Therapy Improves Blood Circulation, Analysis Suggests

Now PAH standard of care, therapy allows several pathways to be targeted at once

Vanda Pinto, PhD avatar

by Vanda Pinto, PhD |

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Illustration shows lungs and the heart; the pulmonary arteries transport blood from the heart into the lungs.

Combination therapy — a treatment approach used to target multiple pathways involved in pulmonary arterial hypertension (PAH) — improves hemodynamics (blood flow) in treatment-naïve patients, according to a new pooled analysis of several studies.

A measure of the resistance to blood flow, called pulmonary vascular resistance (PVR), decreased significantly in patients after combination therapy. This reduction was even more pronounced with triple combination therapy which included prostanoid agents.

“Initial combination therapy leads to remarkable haemodynamic amelioration,” the researchers wrote. “Prostanoids should be considered early, especially in more severely affected patients.”

Prostanoid agents are manmade mimics of the hormone prostacyclin that work by activating signaling pathways that cause blood vessels to relax and widen (vasodilation), improving blood flow. These compounds also prevent platelets from clumping and blocking arteries.

The study, “Haemodynamic effects of initial combination therapy in pulmonary arterial hypertension: a systematic review and meta-analysis,” was published in the journal ERJ Open Research.

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

Several biological pathways are involved in the development of PAH, including the endothelin pathway, the nitric oxide pathway, and the prostacyclin pathway. Using combination therapy to target several pathways at the same time is now considered the standard of care in PAH.

The benefits of combination therapy have been previously shown. For example, in the Phase 3 clinical trial AMBITION (NCT01178073), initial combination therapy with Letairis (ambrisentan) and Adcirca (tadalafil) was found to be superior to either therapy alone in people with PAH.

However, how combination treatment impacts the dynamics of blood flow, or hemodynamics, remains unclear.

Meta-analysis pooled findings from 13 studies, 880 patients

To address this knowledge gap, a team of researchers in Greece and the U.S. conducted a meta-analysis study. They pooled findings from studies that evaluated changes in several hemodynamic parameters in treatment-naïve PAH patients who received combination therapy.

The team searched medical databases for reports that included PAH patients who were treated with combination therapy from the beginning of each study. Data on PVR and other indicators of blood flow and heart function were assessed.

A total of 13 studies were identified that included a total of 880 patients, with a mean age of 52 years, of whom 74% were women. The majority of patients (80.7%) belonged to WHO functional classes 3 and 4, which includes those who are limited in normal activities and may have severe symptoms.

Pooled data showed PVR was reduced by 52% compared to baseline in patients receiving initial combination therapy. With triple combination therapy, which included prostanoids delivered by injection, a greater reduction of 67% in PVR was observed. This effect was more prominent in younger patients with more typical PAH and a lower number of coexisting conditions.

Further analysis showed that compared to baseline, initial combination therapy caused a reduction in mean pulmonary arterial pressure — blood pressure in the lungs — by 12.2 millimeters of mercury (mmHg) and in right atrial pressure — the blood pressure in the upper-right chamber of the heart — by 3.2 mmHg.

The cardiac index — a measure of heart function — and mixed venous oxygen saturation, the amount of oxygen in the blood that returns to the heart from the body, increased.

Four studies, with a total of 194 patients combined, had used a control group of patients on only one therapy. Data from these studies showed that initial combination therapy reduced PVR by 4.2 Wood units compared to monotherapy. Wood units measure the resistance that must be overcome to push blood from the heart’s bottom right chamber to the pulmonary arteries.

Additionally, mean pulmonary arterial pressure and right atrial pressure were decreased, and cardiac index and mixed venous oxygen saturation were increased in patients who received initial combination therapy compared to patients on monotherapy.

The researchers also noted combination therapy used early could potentially restore the thickness, shape, and function of the right ventricle, a process called right ventricle reverse remodeling.

“In this meta-analysis, initial combination therapy was associated with remarkable haemodynamic changes in treatment-naïve PAH patients,” the team wrote. “Treatment delays have deleterious effects in patients’ functional capacity and outcomes, therefore a ‘watch-and-wait’ approach does not help achieving low-risk status and should be avoided.”

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