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Initial macitentan, tadalafil combination therapy shows promise for PAH: OPTIMA

NEW ORLEANS — Initial combination therapy with macitentan and tadalafil yielded hemodynamic and functional improvements and treatment was well tolerated in adults with newly diagnosed pulmonary arterial hypertension, according to data from the OPTIMA study.

Researchers evaluated first-line dual oral combination therapy in 46 treatment-naive patients with PAH. Treatment was initiated on the same day with macitentan (Opsumit, Actelion Pharmaceuticals) 10 mg and tadalafil 20 mg. The tadalafil dose was increased to 40 mg after 8 days.

At 16 weeks, the primary endpoint of pulmonary vascular resistance was reduced by 47% compared with baseline (geometric mean ratio = 0.53; 95% CI, 0.47-0.59; P < .0001), according to results reported at the CHEST Annual Meeting.

“OPTIMA is the first clinical trial that demonstrates a marked hemodynamic improvement with initial oral double combination therapy in PAH,” Olivier Sitbon, MD, PhD, from Université Paris–Sud, told Healio Pulmonology. “These data are meaningful, as pulmonary vascular resistance is a key marker of disease severity in PAH.”

From baseline to 16 weeks, the mean change in cardiac index was 0.91 L/min/m² (95% CI, 0.71-1.11; P < .0001) and mean change in pulmonary arterial pressure was –7.83 mm Hg (95% CI, –11.71 to –3.94; P = .0002), according to the results.

Also at 16 weeks, mean 6-minute walk distance was increased by 35.8 m (P < .0008) and mean NT-proBNP was reduced by 68% (geometric mean ratio = 0.32; 95% CI, 0.23-0.44; P < .0001), according to the new data.

Sixty-three percent of patients exhibited improvements in functional ability, with no worsening in WHO functional class in any patient. Additionally, the number of patients who met at least three low-risk criteria increased from 23.9% at baseline to 68.2% at 16 weeks. The low-risk criteria assessed included WHO functional class I to II, cardiac index > 2.5 L/min/m², mean right atrial pressure < 8 mm Hg, 6-minute walk distance > 440 m, NT-proBNP < 300 ng/L and mixed venous oxygen saturation > 65%, according to the results.

Initial combination therapy was well tolerated overall, according to the researchers. At least one adverse event was reported in 93.5% of patients, with serious adverse events in 28.3%. Three patients discontinued treatment due to adverse events. The most common adverse events were peripheral edema, headache, diarrhea, dyspnea, anemia and asthenia. Decrease in hemoglobin below 10 g/dL occurred in four patients and aminotransferases three times the upper limit of normal in one patient. Three patients died during the study period, with the causes of death attributed to cardiac arrest, heart failure and multiorgan failure with sepsis, according to the results.

OPTIMA was a prospective, multicenter, single-arm, open-label, phase 4 study. Median duration of exposure to macitentan and tadalafil in this study was 605.5 days. At baseline, 78% of patients with PAH were in WHO functional class III and 22% were in class II. Patients were predominantly women (65%), with a mean age of 57 years. The main etiologies were idiopathic PAH (63%) and connective tissue disease-associated PAH (20%).

“These data support the use of macitentan and tadalafil as part of a combination regimen in patients with PAH, and add to the body of evidence supporting initial combination therapy as the standard of care,” Sitbon told Healio Pulmonology. – by Katie Kalvaitis

Reference:

Sitbon O. Pulmonary Hypertension: Characteristics and Treatment. Presented at: CHEST Annual Meeting; Oct. 19-23, 2019; New Orleans.

Disclosure: Sitbon reports he consults for Actelion, Bayer and United Therapeutics.