One Pill, Two Drugs: How a Single-Tablet PAH Therapy Is Reshaping US Practice

Pulmonary arterial hypertension is one of medicine’s most unforgiving diagnoses. The disease, marked by vasoconstriction and progressive remodeling of the small pulmonary vessels, drives up pulmonary vascular resistance until the right side of the heart begins to fail, and without effective treatment it leads to premature death. In the United States, the clinical picture is further complicated by the fact that most patients carry additional cardiometabolic burdens such as obesity, hypertension, and diabetes, which complicate both treatment decisions and outcomes. Now, less than two years after regulators approved the first once-daily, single-tablet combination of an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor for this disease, the first detailed portrait of how American physicians are actually using the regimen has emerged, and it reveals a medical community leaning hard into simplification.

The new study, published in Advances in Therapy, took a deliberately practical approach to an inherently messy question: what does real-world prescribing look like when a novel fixed-dose combination hits the market? Rather than mining insurance claims, researchers conducted structured sixty-minute interviews with fifty US healthcare providers, including physicians, physician assistants, and nurse practitioners specializing in pulmonology, cardiology, or rheumatology. Each provider reviewed up to three eligible patient charts, producing a dataset of 144 adults with Group 1 pulmonary arterial hypertension who had been initiated on macitentan/tadalafil single-tablet combination therapy within ninety days before the interview. Interviews took place in April 2025, capturing the earliest phase of adoption after the March 2024 approval, and data were abstracted at three timepoints: baseline before initiation, a first follow-up at least ninety days afterward, and a most recent visit where available.

The demographics of the cohort tell a story of their own. The median age at initiation was fifty-four years, and roughly seventy percent of patients were women, consistent with the known epidemiology of the disease. Just over half were covered by commercial insurance, and the etiologic spectrum was broad: idiopathic pulmonary arterial hypertension accounted for about half of cases, connective tissue disease-associated disease for nearly twenty-nine percent, and drug- or toxin-induced disease for nine percent. Perhaps most striking, more than eighty-three percent of patients had at least one comorbidity of interest, and a third had three or more. Hypertension led the list at just over thirty-five percent, followed by obstructive sleep apnea and obesity, each affecting more than a quarter of patients. Nearly half the cohort fell into the intermediate-risk category at baseline, and most patients were in World Health Organization functional class II or III, meaning their disease was symptomatic but not yet at the most severe end of the spectrum.

How patients arrived at the single-tablet regimen proved to be the study’s most revealing finding. Just over half, 51.4 percent, were switched from an existing dual regimen of separate endothelin receptor antagonist and phosphodiesterase 5 inhibitor or soluble guanylate cyclase stimulator tablets. Another 28.5 percent were escalated from monotherapy, adding the second drug class by moving directly to the combination pill. The remaining 20.1 percent were entirely naive to these drug classes and began the fixed-dose combination as their first PAH-directed therapy. Among the switch patients, the prior regimens most often contained tadalafil and macitentan, the very same agents in the new pill, but a meaningful subset transitioned from sildenafil, ambrisentan, or bosentan, raising the possibility that agent-level pharmacological differences, not just simplification, contributed to downstream changes. For treatment-naive patients, most providers started the combination directly rather than using a rapid sequential strategy, though about five percent of all patients followed a short monotherapy run-in, often to test tolerability or navigate formulary hurdles.

When researchers asked providers why they chose the single-tablet regimen, the answer was emphatic: pill burden. Seventy-seven percent cited reduction in pill burden as a reason for initiation, thirty-nine percent pointed to a perceived favorable clinical profile, and thirty-five percent expressed concern about patient compliance with individual-tablet combinations. The rationale shifted predictably by treatment archetype. For naive patients, forty-eight percent of initiations were driven by alignment with clinical guidelines, reflecting the growing consensus, anchored by the AMBITION trial, that upfront dual therapy with an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor improves outcomes in newly diagnosed patients with functional class II or III symptoms. For patients escalated from monotherapy, seventy-one percent of decisions were motivated by a perceived need for additional therapy. These provider-reported reasons echo earlier qualitative work from the A DUE trial program, in which both patients and clinicians described the single-tablet approach as reducing medication-management burden and improving convenience.

The exploratory outcomes, though framed cautiously by the authors, are the numbers most likely to capture attention. Among patients who received the fixed-dose combination without concurrent initiation or escalation of prostacyclin or activin signaling inhibitor therapy, and who had paired baseline and follow-up measurements, three-month changes were favorable across the board. Six-minute walk distance, the standard measure of exercise capacity in pulmonary hypertension, rose by a mean of 51.0 meters, from 355.2 to 406.2 meters, in thirty-six patients with paired data. Brain natriuretic peptide, a biomarker of cardiac stress that correlates with disease severity and prognosis, fell by a mean of 167.8 picograms per milliliter, from 357.0 to 189.2, in twenty-nine patients. And PAH-related hospitalizations dropped from 0.18 to 0.05 events per patient over roughly three months among sixty-five patients assessed. Notably, patients who initiated the combination remained on therapy without discontinuation throughout the follow-up window.

The authors are careful, and rightly so, to keep these findings in perspective. The study was retrospective, non-comparative, and not powered for hypothesis testing. There was no control group, no adjustment for confounding, and no multiplicity correction, so the improvements cannot be attributed causally to the single-tablet formulation itself. Patients switched from sildenafil or ambrisentan to macitentan or tadalafil may have benefited from agent-level differences, as prior meta-analyses have documented clinical changes after switching from bosentan or ambrisentan to macitentan. Adherence and persistence were not measured directly, so the hypothesis that simplification improves real-world medication-taking remains untested in this cohort. Selection bias is another concern: providers chose which charts to review, patients who discontinued within thirty days were excluded, and compensated participation may limit generalizability. Chart abstraction relied on provider recall without independent adjudication of diagnoses or hospitalizations, and misclassification with comorbidity-associated pulmonary hypertension cannot be excluded.

Even with those caveats, the study fills a genuine gap in the evidence base. Previous research has shown that real-world PAH treatment frequently diverges from guideline recommendations, and that nearly two-thirds of US patients are treated at non-accredited, low-volume centers that are more likely to prescribe monotherapy than expert centers. Against that backdrop, the rapid uptake of a guideline-concordant dual regimen, including as first-line therapy in treatment-naive patients, suggests that removing the friction of multiple prescriptions may itself be a lever for better care. The US context matters here: American patients tend to present with higher rates of obesity and comorbidity than European cohorts, and they face greater access and reimbursement complexity, which is why international registry findings do not always translate directly. Fixed-dose combinations have been shown in other disease areas to improve adherence compared with free-equivalent combinations, making the PAH application a natural and consequential experiment.

What emerges from this early snapshot is a portrait of pragmatic adoption. Physicians are using the macitentan/tadalafil single tablet most often to consolidate existing dual therapy, but they are also escalating monotherapy patients with it and, in a substantial minority of cases, starting newly diagnosed patients on it directly, frequently at the 10 milligram/20 milligram titration dose. Many patients continue on the combination alongside prostacyclin agents or the newer activin signaling inhibitor sotatercept, reflecting the expanding multi-pathway armamentarium that now defines modern PAH management. The authors call for longitudinal and comparative research to establish whether the favorable three-month signals in walk distance, biomarkers, and hospitalizations persist, and whether simplification genuinely translates into better adherence and durability. For now, the message for the roughly 144 patients in this cohort, and the many more like them, is that the era of the single-pill PAH regimen has arrived in American clinics, and early experience suggests it is being embraced for exactly the reason its developers intended: fewer pills, simpler regimens, and, perhaps, better outcomes.

Subject of Research: Real-world use of macitentan/tadalafil single-tablet combination therapy in US patients with pulmonary arterial hypertension

Article Title: Real-World Characteristics, Treatment Patterns, and Clinical Outcomes of Patients Initiated on Macitentan/Tadalafil Single-Tablet Combination Therapy in the United States

Article References: Krishnan, M., Kolaitis, N. A., Sandros, M., Adhia, A. D., Lopez, D., Gearhart, N., Salomon, A. K., & Ryan, J. J. (2026). Real-World Characteristics, Treatment Patterns, and Clinical Outcomes of Patients Initiated on Macitentan/Tadalafil Single-Tablet Combination Therapy in the United States. Advances in Therapy. https://doi.org/10.1007/s12325-026-03811-0

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03811-0

Keywords: pulmonary arterial hypertension, macitentan, tadalafil, fixed-dose combination, single-tablet therapy, endothelin receptor antagonist, PDE5 inhibitor, pill burden, real-world evidence, treatment patterns, 6-minute walk distance, BNP