Combo Improves Blood Flow in Pulmonary Arterial Hypertension

Ingrid Hein

October 28, 2019

For patients with newly diagnosed pulmonary arterial hypertension, the combination of macitentan (Opsumit, Actelion Pharmaceuticals) plus tadalafil (Adcirca, Eli Lilly) improves hemodynamics, function, and risk profile, results from the OPTIMA study show.

"This is another demonstration that initial combination therapy is particularly efficacious in patients with PAH," said Olivier Sitbon, MD, PhD, from Université Paris–Sud.

"Combination therapy is becoming the treatment of choice for the vast majority of patients with PAH; here we have another option," he reported at CHEST 2019 in New Orleans.

Results from the 2015 AMBITION study showed that the combination of ambrisentan (Letairis, Gilead Sciences), an endothelin-receptor antagonist, plus tadalafil, a phosphodiesterase type-5 inhibitor, was more effective than monotherapy.

"So we know for the long term, initial combination therapy is efficacious and results in a delay of progression, compared with monotherapy," Sitbon said. In fact, the AMBITION findings led to the approval of the combination of ambrisentan and tadalafil for patients with pulmonary arterial hypertension, as reported by Medscape Medical News.

"But we didn't get any hemodynamic results from that study," he said.

OPTIMA is the first study to show hemodynamic results for combination therapy, he told Medscape Medical News. "Until now, we've had very little information."

With macitentan and tadalafil, "we observed a major hemodynamic improvement," with a decrease in pulmonary muscular resistance of almost 50% and a reduction in pulmonary vascular remodeling of 47%, said Sitbon.

"There was also improvement in cardiac output, a decrease in pulmonary artery pressure, and a major decrease — of about 70% — in the level of NT-proBNP, which is a very important biomarker for disease severity."

"We know it's good news when patients reach a normal level of NT-proBNP," he added.

OPTIMA Trial

The 46 participants in the OPTIMA trial — which was sponsored by Actelion Pharmaceuticals — had been diagnosed with pulmonary arterial hypertension in the previous 6 months, and all were treatment-naïve. All had a WHO functional classification of II or III and a 6-minute walk distance of less than 50 meters (164 feet).

In the study cohort, the condition was idiopathic, heritable, drug- or toxin-induced, associated with connective tissue disease, or associated with HIV infection. Two participants — one with suspected pulmonary veno-occlusive disease who saw no benefit from the drug combination and withdrew from the study and another whose diagnosis was reclassified as coronary heart disease — were excluded from the analysis.

At baseline, right heart catheterization screening showed that mean resting pulmonary arterial pressure was at least 25 mm Hg, pulmonary artery wedge pressure or left ventricular end diastolic pressure was 15 mm Hg or less, and pulmonary vascular remodeling was at least 400 dyne-second per cm−5 for wedge pressure below 12 mm Hg or at least 500 dyne-second per cm−5 for wedge pressure from 12 to 15 mm Hg.

There was a 47% reduction in the primary study end point of the ratio of pulmonary vascular remodeling from baseline to 16 weeks (< .0001). And 87% of the participants had a decrease of at least 30% in that ratio from baseline to week 16.

Mean 6-minute walk distance improved from 352 m (1156 feet) at baseline to 388 m (1273 feet) at week 16 (P = .0008). And median NT-proBNP level decreased from 1456.8 ng/L at baseline to 404.2 ng/L at week 16 (P < .0001).

At week 16, WHO functional classification had not worsened in any study participant, and had improved in 63%. Approximately 70% of participants met the criteria for WHO functional classification I or II at week 16, whereas at baseline, only 22% met the criteria for functional classification II and none met the criteria for functional classification I.

"Our patients clearly improved with this combination," Sitbon reported. "We did not look at quality-of-life indicators, but when you markedly improve hemodynamics and personal capacity, you improve many aspects of daily life."

This is an "encouraging" study, but it "should not be considered an equivalent trial to longer morbidity-driven end-point studies," Victor Test, MD, from Texas Tech University Health Sciences Center in Lubbock, added in a news release.

However, the findings add "strength to the evidence for upfront dual oral therapy," he noted.

CHEST 2019: American College of Chest Physicians Annual Meeting. Presented October 21, 2019.

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