Fixed-Dose Combination Pill Bests Monotherapy for Pulmonary Arterial Hypertension

Kelly Chin, MD

Credit: ACC

A fixed-dose combination pill of macitentan and tadalafil outperformed monotherapy of either drug in patients with pulmonary arterial hypertension (PAH), according to new findings from the Phase III A DUE Study.¹

The results, presented at the American College of Cardiology (ACC) 2023 Annual Scientific Sessions in New Orleans, Louisiana, indicated the combination of macitentan (10 mg) and tadalafil (40 mg) had approximately double the reduction in pulmonary vascular resistance (PVR) compared to either drug alone.

“Across many studies, we’re seeing that more is better in terms of lowering PVR, and what we get with one medication is, for many patients, just not enough,” said Kelly Chin, MD, Director of the Pulmonary Hypertension Program, UT Southwestern Medical Center. “I would strongly recommend combination therapy with two medications initially for the majority of patients, and this combination has significant evidence that it’s effective and well tolerated.”

Current guidelines indicate the use of two or more agents in PAH treatment may provide extra benefit for patients. The US Food and Drug Administration (FDA) has approved several agents for the treatment of PAH, including macitentan and tadalafil. The A DUE trial is the first to study the efficacy and safety of a fixed-dose combination of these drugs in a single tablet compared with either medication alone.

Investigators enrolled 187 patients with PAH who had experienced limitations in physical activity but were comfortable at rest (World Health Organization classification system, class II and II PAH). Most of the included patients were women and the average age ranged from 49 to 53 years in the treatment groups.

Approximately half of the study population were not currently taking medications for PAH. Investigators randomly assigned half of the patients to take the fixed-dose combination pill daily. One-quarter of patients were assigned to either macitentan or tadalafil, but not their combination in a tablet.

Of those already taking macitentan or tadalafil at the beginning of the study, two-thirds were assigned to receive the two-drug combination, and one-third were assigned to continue taking their individual drug. The primary endpoint was defined as the pulmonary vascular resistance (PVR) ratio to baseline at Week 16. Of the 187 patients included in the study, 108 were randomized to the fixed-dose combination pill, 35 to macitentan alone, and 44 to tadalafil alone.

When comparing the fixed-dose combination with macitentan monotherapy, data showed PVR decreased by 45% in the fixed-dose combination arm and by 23% in the monotherapy arm. Compared to tadalafil monotherapy, PVR decreased by 44% in the fixed-dosed combination arm and 22% in the monotherapy arm.

At week 16, individuals taking the combination pill indicated a significantly greater reduction in PVR compared to the baseline than those taking either drug alone, meeting the trial’s primary endpoint. Although the study could not draw conclusions on symptoms or cardiovascular outcomes, investigators note the data strengthen the understood benefit of multiple drugs for PAH management.

In addition, patients taking the two-drug combination therapy were more likely to discontinue their assigned therapy due to adverse events, with anemia, hypotension, and swelling as the most common side effects. Investigators noted it is typical for individuals taking two drugs to experience more side effects than monotherapy, with study results suggesting no evidence of any previously unknown side effects.

“We were very happy with the results,” Chin added. “PVR fell in both patients who were on one therapy and patients who were on two, but it was a much larger decrease with fixed-dose combination therapy.”

References

1. Fixed-dose combination pill outperforms monotherapy for pulmonary hypertension. American College of Cardiology. https://www.acc.org/About-ACC/Press-Releases/2023/03/06/14/01/Fixed-Dose-Combination-Pill-Outperforms-Monotherapy-for-PH. Published March 6, 2023. Accessed March 6, 2023.